Process for the preparation of 7-fluoro-6-amino-2H-1,4-benzoxazin-3(4H)-one

Abstract

This invention relates to the synthesis of 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one. A preparation method is disclosed, comprising the following steps: using p-fluoroaniline (Ⅰ) as a starting material, undergoing acylation, halogenation, etc., followed by etherification and cyclization to generate 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V), and then nitrifying and hydrogenating to obtain 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one (VI). In this synthesis process, the existing technology overcomes the generation of hydrogen fluoride gas that corrodes equipment and the occurrence of isomerization, providing a green and environmentally friendly new process for the preparation of 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one.

Description

Technical Field

[0001] This invention relates to the field of fine chemical trifluoropesticide and intermediate preparation technology, specifically to a method for preparing 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one. Background Technology

[0002] Propylene flumetsulam is an phthalimide herbicide and a typical contact herbicide, but it cannot be used for post-emergence foliar application. When propylene flumetsulam is applied to the soil surface, the herbicide is absorbed by soil particles, forming a treatment layer. When weeds germinate, seedlings that come into contact with this treatment layer wither and die. In foliar application, it is absorbed by plant buds and leaves, translocated within the plant, and acts rapidly on the leaves of susceptible weeds, causing protoporphyrin accumulation and increased cell membrane peroxidation, leading to irreversible damage to the cell membrane structure and function of susceptible weeds. After application, weed leaves show necrotic spots, and weeds often wilt, turn white, and die within 24-28 hours. It is mainly used to control annual broadleaf weeds and some grassy weeds.

[0003] 7-Fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one is a key intermediate in the synthesis of propyzinamide.

[0004] Currently, the main synthetic intermediate process routes are as follows:

[0005] Route 1: Starting with 2,4-difluoronitrobenzene, the process involves hydrolysis, etherification, and hydrogenation reduction to form a cyclization ring. In this route, hydrolysis results in a 15% phenol byproduct. Alternatively, using 1,5-difluoro-2,4-dinitrobenzene as a raw material, direct etherification leads to isomerization byproducts, low yield, and the production of hydrogen fluoride byproducts that corrode equipment, making industrialization difficult and costly.

[0006] Route 2: Using 2-nitro-5-fluorophenol as a raw material, it is prepared by reaction. This method is simple to operate and has high yields in each step of the reaction, but the price of the raw material 2-nitro-5-fluorophenol is relatively high, which greatly increases the cost and is not conducive to industrial production.

[0007] Route 3: Using m-fluorophenol as a raw material, it is prepared by etherification and nitration. This route has many side reactions during nitration, especially the ether bond is prone to breakage and oxidation during nitration; it is not conducive to industrial production.

[0008] Route 4: The product is prepared by reaction using m-difluorobenzene as a raw material. While m-difluorobenzene is a relatively inexpensive raw material, its nitro group orientation is complex during nitration, resulting in numerous byproducts and difficult separation, making it relatively difficult to prepare a high-content product.

[0009] Of the above technical solutions, Route 1 is currently the most mature for industrialization. However, during production, hydrolysis isomerization accounts for 15%, and etherification also involves isomerization side reactions. Furthermore, hydrogen fluoride gas is generated as a byproduct of post-processing, causing severe equipment corrosion. In view of these problems, this invention solves the issues of equipment corrosion and high costs in industrial production, achieving green industrialization and improving market competitiveness. Summary of the Invention

[0010] The purpose of this invention is to overcome the problems of high isomerization rates and equipment corrosion caused by hydrogen fluoride byproducts in the hydrolysis preparation of phenols in the existing technology for the preparation of 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one. This invention provides a new, green, and environmentally friendly process for the preparation of 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one. The preparation route of this application has low raw material costs, avoids isomerization, does not produce hydrogen fluoride gas that corrodes equipment, and improves the conversion rate and selectivity of 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one.

[0011] To achieve the above objectives, a first aspect of the present invention provides a method for preparing 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one, wherein the preparation method comprises:

[0012] (1) The compound shown in formula (Ⅰ) is subjected to a first acylation reaction with a first acylation reagent, and then a first halogenation reaction is carried out by adding a first halogenation reagent to obtain the compound shown in formula (Ⅱ);

[0013] (2) In the presence of a polar solvent, a first catalyst and a first acid-binding agent, the compound shown in formula (II) and the compound shown in formula (VII) undergo a first etherification reaction to obtain the compound shown in formula (IV); under cyclization conditions, the compound shown in formula (IV) undergoes a first cyclization reaction to obtain the compound shown in formula (V).

[0014] (3) The compound shown in formula (V) was subjected to nitration and hydrogenation to obtain 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one shown in formula (VI);

[0015]

[0016] Where X is Cl, Br or I, R1 is -OCH3, -OH or -NH2, and R is a hydroxyl group or a halogen.

[0017] A second aspect of the present invention provides a method for preparing 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one, wherein the preparation method comprises:

[0018] (i) The compound shown in formula (I) is subjected to a second acylation reaction with a second acylation reagent, and then a second halogenation reaction is carried out with a second halogenation reagent to obtain the compound shown in formula (III);

[0019] (ii) In the presence of a polar solvent, a second catalyst and a second acid-binding agent, the compound shown in formula (Ⅲ) is subjected to a second etherification cyclization reaction to directly obtain the compound shown in formula (V);

[0020] (iii) The compound shown in formula (V) was subjected to nitration and hydrogenation to obtain 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one shown in formula (VI).

[0021]

[0022] Where X is Cl, Br or I, and R2 is a halogen.

[0023] Through the above technical solution, the present invention solves the problems of large isomerization and equipment corrosion caused by byproducts during the preparation of 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one in the process of preparing phenol in the prior art. It realizes the absence of isomerization side reactions in the etherification reaction and provides a green and environmentally friendly preparation process for 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one. Detailed Implementation

[0024] The endpoints and any values ​​of the ranges 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 endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0025] The first aspect of this invention provides a method for preparing 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one, wherein the process route (denoted as process A) includes:

[0026] (1) The compound shown in formula (Ⅰ) is subjected to a first acylation reaction with a first acylation reagent, and then a first halogenation reaction is carried out by adding a first halogenation reagent to obtain the compound shown in formula (Ⅱ);

[0027] (2) In the presence of a polar solvent, a first catalyst and a first acid-binding agent, the compound shown in formula (II) and the compound shown in formula (VII) undergo a first etherification reaction to obtain the compound shown in formula (IV); under cyclization conditions, the compound shown in formula (IV) undergoes a first cyclization reaction to obtain the compound shown in formula (V).

[0028] (3) The compound shown in formula (V) was subjected to nitration and hydrogenation to obtain 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one shown in formula (VI);

[0029]

[0030] Where X is Cl, Br or I, R1 is -OCH3, -OH or -NH2, and R is a hydroxyl group or a halogen.

[0031] In some preferred embodiments of the present invention, preferably, in step (1), the conditions of the first acylation reaction include: the first acylation temperature is 30-70°C, preferably 30-60°C; the first acylation time is 1-6h, preferably 3-4h.

[0032] In some preferred embodiments of the present invention, the first acylation reagent is preferably selected from acetic anhydride or acetyl chloride.

[0033] In some preferred embodiments of the present invention, preferably, the molar ratio of the first acylation reagent to the compound shown in formula (I) is 1-1.5:1, more preferably 1.1-1.3:1.

[0034] In some preferred embodiments of the present invention, the first acylation reagent is preferably added dropwise under stirring.

[0035] In some preferred embodiments of the present invention, the conditions for the first halogenation reaction include: a first halogenation temperature of 0-60°C, more preferably, a chlorination temperature of 40-50°C, and a bromination temperature of 5-15°C; and a first halogenation time of 1-6 h, preferably 3-4 h.

[0036] In some preferred embodiments of the present invention, the first halogenating agent is preferably selected from at least one of sodium bromate and hydrogen peroxide combination, chlorine, sulfonyl chloride, thionyl chloride, N-chlorosuccinimide, dichlorohydantoin, dibromohydantoin, N-bromosuccinimide and bromine, preferably chlorine or bromine.

[0037] In some preferred embodiments of the present invention, preferably, the molar ratio of the first halogenating agent to the compound shown in formula (I) is 1-3:1, more preferably 1.1-1.3:1.

[0038] In some preferred embodiments of the present invention, preferably, in step (1), the compound shown in formula (I) is added to an organic solvent, wherein the organic solvent is selected from at least one of dichloroethane, dichloromethane, acetic acid, toluene and acetonitrile, and more preferably, the organic reagent is dichloroethane.

[0039] In some preferred embodiments of the present invention, preferably, after the first halogenation reaction, an alkaline aqueous solution is used to adjust the pH of the system to neutral.

[0040] In some preferred embodiments of the present invention, preferably, in step (2), the compound shown in formula (II) is subjected to a first etherification reaction with the compound shown in formula (VII). This etherification reaction may involve an intermediate process, in which water or alcohol may be present in a polar solvent, causing -X to be converted to -OH.

[0041] In some preferred embodiments of the present invention, preferably, the compound represented by formula (VII) is selected from at least one of methyl haloacetate, ethyl haloacetate, glycolic acid, methyl glycolate and hydroxyacetamide, more preferably, the compound represented by formula (VII) is selected from methyl chloroacetate or methyl glycolate.

[0042] In some preferred embodiments of the present invention, preferably, the molar ratio of the compound shown in formula (II) to the compound shown in formula (VII) is 1:1-2, more preferably, the molar ratio is 1:1.1-1.3.

[0043] In some preferred embodiments of the present invention, preferably, the first acid-binding agent is selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, pyridine, triethylamine, tetramethylethylenediamine, dimethylpropylenediamine, tetramethylpropylenediamine, N,N'-dimethylethylenediamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, N,N-dimethylaniline and diisopropylethylamine, preferably potassium carbonate and / or sodium hydroxide.

[0044] In some preferred embodiments of the present invention, preferably, the molar ratio of the compound represented by formula (II) to the first acid-binding agent is 1:2-4, more preferably 1:2.2-2.4.

[0045] In some preferred embodiments of the present invention, preferably, the first catalyst is a copper salt; more preferably, the copper salt is selected from at least one of copper chloride, copper acetate, cuprous chloride, cuprous iodide, cuprous bromide, copper acetylacetonate, copper acetate, copper bromide, copper iodide, copper trifluoroacetate, copper trifluoromethanesulfonate, copper phenylacetate, copper trifluoroacetylacetonate, copper hexafluoroacetylacetonate, copper ethylacetoacetate, copper triphenylphosphine bromide, and copper benzoylacetone, preferably cuprous chloride.

[0046] In some preferred embodiments of the present invention, preferably, the conditions for the first etherification reaction include: a first etherification temperature of 30-200°C, preferably 70-150°C; and a first etherification time of 4-15 h, preferably 9-10 h.

[0047] In some preferred embodiments of the present invention, preferably, the first cyclization reaction includes adding an acid to the product obtained from the first etherification reaction and reacting it with a compound of formula (Ⅳ).

[0048] In some preferred embodiments of the present invention, the acid is preferably selected from at least one of sulfuric acid, hydrochloric acid and phosphoric acid, and more preferably hydrochloric acid.

[0049] In some preferred embodiments of the present invention, preferably, the conditions for the first cyclization reaction include: a first cyclization temperature of 90-110°C and a first cyclization reaction time of 5-6 hours.

[0050] In some preferred embodiments of the present invention, preferably, in step (2), the polar solvent is selected from solvent A, or a combination of solvent A and solvent B, wherein solvent A is selected from at least one of methanol, ethanol, n-butanol, isopropanol, tert-butanol and water, and solvent B is selected from at least one of N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone, preferably N,N-dimethylformamide and water.

[0051] In some preferred embodiments of the present invention, preferably, step (3) further includes the following steps: extracting the compound of formula (V) after nitration, dissolving it in methanol solution, transferring it to an autoclave, adding palladium on carbon, and introducing hydrogen gas.

[0052] In some preferred embodiments of the present invention, preferably, the conditions for the nitration reaction in step (3) include: nitration temperature of 10-70℃, preferably 20-40℃; nitration time of 2-6h, preferably 3-4h.

[0053] In some preferred embodiments of the present invention, preferably, a nitrifying agent is added to the nitration reaction; more preferably, the nitrifying agent is concentrated sulfuric acid and concentrated nitric acid.

[0054] In some preferred embodiments of the present invention, preferably, the added concentrated sulfuric acid is 98wt% sulfuric acid, and the mass ratio of the added concentrated sulfuric acid to the compound shown in formula (V) is 3-5:1, preferably 3-4:1.

[0055] In some preferred embodiments of the present invention, preferably, the concentration of added nitric acid is 65 wt%, and the molar ratio of the nitric acid to the compound shown in formula (V) is 1-1.5:1, preferably 1.1-1.2:1.

[0056] In some preferred embodiments of the present invention, the hydrogenation reaction is preferably carried out in the presence of a hydrogenation catalyst.

[0057] In some preferred embodiments of the present invention, the conditions for the hydrogenation reaction preferably include: the hydrogenation temperature is 30-100°C, preferably 40-60°C; and the hydrogen pressure is 1-3 MPa, preferably 1.5-1.8 MPa.

[0058] In some preferred embodiments of the present invention, the hydrogenation catalyst is preferably selected from palladium on carbon or Raney nickel, and more preferably, palladium on carbon.

[0059] In some preferred embodiments of the present invention, preferably, the palladium content in the palladium carbon is 5 wt%, based on the total amount of palladium on carbon.

[0060] In some preferred embodiments of the present invention, preferably, the mass ratio of palladium to the compound shown in formula (V) is 0.02-0.05:1.

[0061] A second aspect of the present invention provides a method for preparing 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one, wherein the process route (denoted as process B) includes:

[0062] (i) The compound shown in formula (I) is subjected to a second acylation reaction with a second acylation reagent, and then a second halogenation reaction is carried out with a second halogenation reagent to obtain the compound shown in formula (III);

[0063] (ii) In the presence of a polar solvent, a second catalyst and a second acid-binding agent, the compound shown in formula (Ⅲ) is subjected to a second etherification cyclization reaction to directly obtain the compound shown in formula (V);

[0064] (iii) The compound shown in formula (V) was subjected to nitration and hydrogenation to obtain 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one shown in formula (VI).

[0065]

[0066] Where X is Cl, Br or I, and R2 is a halogen.

[0067] In some preferred embodiments of the present invention, R2 is preferably Cl or Br.

[0068] In some preferred embodiments of the present invention, preferably, in step (i), the conditions for the second acylation reaction include: the second acylation temperature is 30-70°C, preferably 30-60°C; and the second acylation time is 1-6 hours, preferably 3-4 hours.

[0069] In some preferred embodiments of the present invention, the second acylation reagent is preferably selected from haloacetyl chloride, and more preferably chloroacetyl chloride.

[0070] In some preferred embodiments of the present invention, preferably, the molar ratio of the second acylation reagent to the compound shown in formula (I) is 1-1.5:1, more preferably 1.1-1.3:1.

[0071] In some preferred embodiments of the present invention, the second acylation reagent is preferably added dropwise under stirring.

[0072] In some preferred embodiments of the present invention, the conditions for the second halogenation reaction include: a second halogenation temperature of 0-60°C, more preferably, a chlorination temperature of 40-50°C, and a bromination temperature of 5-15°C; and a second halogenation time of 1-6 h, preferably 3-4 h.

[0073] In some preferred embodiments of the present invention, the second halogenating agent is preferably selected from at least one of sodium bromate and hydrogen peroxide combination, chlorine, sulfonyl chloride, thionyl chloride, N-chlorosuccinimide, dichlorohydantoin, dibromohydantoin, N-bromosuccinimide and bromine, preferably chlorine or bromine.

[0074] In some preferred embodiments of the present invention, preferably, the molar ratio of the second halogenating agent to the compound shown in formula (I) is 1-3:1, more preferably 1.1-1.3:1.

[0075] In some preferred embodiments of the present invention, preferably, in step (i), the compound shown in formula (I) is added to an organic solvent, wherein the organic solvent is selected from at least one of dichloroethane, dichloromethane, acetic acid, toluene and acetonitrile, and more preferably, the organic reagent is dichloroethane.

[0076] In some preferred embodiments of the present invention, preferably, after the second halogenation reaction, an alkaline aqueous solution is selected to adjust the pH of the system to neutral.

[0077] In some preferred embodiments of the present invention, preferably, in step (ii), the compound shown in formula (Ⅲ) undergoes a second etherification cyclization reaction, which is a one-step reaction.

[0078] In some preferred embodiments of the present invention, the second acid-binding agent is preferably selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, pyridine, triethylamine, tetramethylethylenediamine, dimethylpropylenediamine, tetramethylpropylenediamine, N,N'-dimethylethylenediamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, N,N-dimethylaniline, and diisopropylethylamine, and is preferably potassium carbonate and / or sodium hydroxide.

[0079] In some preferred embodiments of the present invention, preferably, the molar ratio of the compound represented by formula (Ⅲ) to the second acid-binding agent is 1:1-3, more preferably 1:2.1-2.3.

[0080] In some preferred embodiments of the present invention, preferably, the second catalyst is a copper salt, more preferably, the copper salt is selected from at least one of copper chloride, copper acetate, cuprous chloride, cuprous iodide, cuprous bromide, copper acetylacetone, copper acetate, copper bromide, copper iodide, copper trifluoroacetate, copper trifluoromethanesulfonate, copper phenylacetate, copper trifluoroacetylacetone, copper hexafluoroacetylacetone, copper ethylacetoacetate, copper triphenylphosphine bromide, and copper benzoylacetone, preferably cuprous chloride.

[0081] In some preferred embodiments of the present invention, the conditions for the second etherification cyclization reaction preferably include: an etherification cyclization temperature of 40-180°C, preferably 60-120°C; and an etherification cyclization time of 1-6 hours, preferably 3-4 hours. During this reaction, an intermediate process may occur, where water or alcohol may be present in the polar solvent, converting -X to -OH.

[0082] In some preferred embodiments of the present invention, preferably, in step (ii), the second etherification cyclization reaction is carried out directly in the above reaction system.

[0083] In some preferred embodiments of the present invention, preferably, in step (ii), the polar solvent is selected from solvent A, or a combination of solvent A and solvent B, wherein solvent A is selected from at least one of methanol, ethanol, n-butanol, isopropanol, tert-butanol and water, and solvent B is selected from at least one of N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone, preferably N,N-dimethylformamide and water.

[0084] In some preferred embodiments of the present invention, preferably, step (iii) further includes the following steps: extracting the compound of formula (v) after nitration, dissolving it in methanol solution after desolvation, transferring it to an autoclave, adding palladium on carbon, and introducing hydrogen gas.

[0085] In some preferred embodiments of the present invention, preferably, the conditions for the nitration reaction in step (iii) include: a nitration temperature of 10-70°C, preferably 20-40°C; and a nitration time of 2-6 h, preferably 3-4 h.

[0086] In some preferred embodiments of the present invention, preferably, a nitrifying agent is added to the nitration reaction, wherein the nitrifying agent is concentrated sulfuric acid and concentrated nitric acid.

[0087] In some preferred embodiments of the present invention, preferably, the added concentrated sulfuric acid is 98wt% sulfuric acid, and the mass ratio of the added concentrated sulfuric acid to the compound shown in formula (V) is 3-5:1, preferably 3-4:1.

[0088] In some preferred embodiments of the present invention, preferably, the concentration of the added concentrated nitric acid is 65 wt%, and the molar ratio of the nitric acid to the compound shown in formula (V) is 1-1.5:1, preferably 1.1-1.2:1.

[0089] In some preferred embodiments of the present invention, preferably, in step (iii), the hydrogenation reaction is carried out in the presence of a hydrogenation catalyst.

[0090] In some preferred embodiments of the present invention, the conditions for the hydrogenation reaction preferably include: a hydrogenation temperature of 30-100°C, preferably 40-60°C; and a hydrogen pressure of 1-3 MPa, preferably 1.5-1.8 MPa.

[0091] In some preferred embodiments of the present invention, the hydrogenation catalyst is preferably selected from palladium on carbon or Raney nickel, and more preferably, palladium on carbon.

[0092] In some preferred embodiments of the present invention, preferably, the palladium content in the palladium carbon is 5 wt%, based on the total amount of palladium on carbon.

[0093] In some preferred embodiments of the present invention, preferably, the mass ratio of palladium to the compound shown in formula (V) is 0.02-0.05:1.

[0094] The present invention will be described in detail below through examples. In Examples 1-8 below, the parameters were measured by HPLC and liquid chromatography (Agilent HPLC 1260).

[0095] In the following embodiments,

[0096] Unless otherwise specified, all raw materials used are commercially available products.

[0097] Example 1

[0098] (1) Acylation-halogenation reaction: In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 11.5 g of 4-fluoroaniline (Ⅰ) (0.1 mol, 98%, purchased from Aladdin) and 33 mL of dichloroethane (DCE) were added. The temperature was raised to 50 °C, and 12.3 g of acetic anhydride was added dropwise. The mixture was stirred and the first acylation reaction was carried out for 2 h. The reaction of the raw material was detected by HPLC. The temperature was lowered to 40 °C, and 8.5 g of chlorine gas was introduced to carry out the first halogenation reaction. After the reaction of the raw material was completed, the temperature was lowered and alkaline water was added. The solid precipitated and filtered to obtain 18.2 g of product containing 2-chloro-4-fluoroacetaniline (Ⅱ). The content of 2-chloro-4-fluoroacetaniline (Ⅱ) in the product was 98%, and the yield was 95% (based on 4-fluoroaniline (Ⅰ)).

[0099] (2) Etherification cyclization reaction: 2-chloro-4-fluoroacetanilide (II) prepared in the previous step was added to a reaction flask, along with 29.5 g of potassium carbonate (first acid-binding agent), 200 mL of N,N-dimethylformamide, 5 mL of water, 13.2 g of methyl chloroacetate (formula (VII)), and 0.9 g of cuprous chloride. The mixture was kept at 100 °C and stirred for 9 hours to carry out the first etherification reaction, yielding 2-acetyl-5-fluorophenylacetic acid methyl ether (IV). The temperature was lowered to 80 °C, hydrochloric acid was added, and the mixture was kept at 80 °C for 5 hours to obtain 14.7 g of a product containing 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V). The content of 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V) in the product was 98%, and the yield was 90% (based on 2-chloro-4-fluoroacetanilide (II)).

[0100] (3) Nitration-hydrogenation reaction: 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V) prepared in the previous step was added to a reaction flask, along with 44.1 g of concentrated sulfuric acid. The mixture was kept at 30°C, and 9.2 g of concentrated nitric acid was added dropwise. The reaction was allowed to proceed for 4 hours. After the reaction was complete, DCE was added for extraction to separate the layers and remove the solvent. 100 mL of methanol was added, and the mixture was poured into a high-pressure reactor. 0.3 g of palladium on carbon was added, and hydrogen gas was introduced. The mixture was kept at 50°C and 1.6 MPa. The hydrogenation reaction was carried out, and after the reaction was completed, palladium on carbon was filtered off and the solvent was removed to obtain 14.4 g of product containing 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one (VI). The content of 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one (VI) in the product was 98%, and the yield was 90.5% (based on 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V)).

[0101] Example 2

[0102] (1) Acylation-halogenation reaction: In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 11.5 g of 4-fluoroaniline (Ⅰ) (0.1 mol, 98%, purchased from Aladdin) and 33 mL of dichloroethane (DCE) were added. The temperature was raised to 50 °C, and 13.6 g of chloroacetyl chloride was added dropwise. The mixture was stirred and the second acylation reaction was carried out for 2 h. HPLC analysis showed that the raw material was complete. The temperature was lowered to 10 °C, and 17.6 g of bromine was added dropwise. The second halogenation reaction was carried out. After the raw material was complete, the temperature was lowered and alkaline water was added. The solid precipitated and filtered to obtain 26.0 g of product containing N-(2-bromo-4-fluorophenyl)-2-chloroacetamide (Ⅲ). The content of N-(2-bromo-4-fluorophenyl)-2-chloroacetamide (Ⅲ) in the product was 98%, and the yield was 96% (based on 4-fluoroaniline).

[0103] (2) Etherification cyclization reaction: N-(2-bromo-4-fluorophenyl)-2-chloroacetamide (III) prepared in the previous step was added to a reaction flask, along with 29.8 g of potassium carbonate, 200 mL of N,N-dimethylformamide, 5 mL of water, and 0.9 g of cuprous chloride. The mixture was kept at 80 °C and stirred for 9 hours to carry out the second etherification reaction, yielding 14.6 g of product containing 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V). The content of 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V) in the product was 98%, and the yield was 90% (based on N-(2-bromo-4-fluorophenyl)-2-chloroacetamide (III)).

[0104] (3) Nitration-hydrogenation reaction: The 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V) prepared in the previous step was added to a reaction flask, along with 45g of concentrated sulfuric acid. The mixture was kept at 30°C, and 10.0g of concentrated nitric acid was added dropwise. The reaction time was 6 hours. After the nitration reaction was completed, DCE was added for extraction and separation. 100mL of methanol was added, and the mixture was poured into a high-pressure reactor. 0.3g of palladium on carbon was added, and hydrogen gas was introduced. The mixture was kept at 50°C and 1.6M. Pa was subjected to hydrogenation reaction. After the reaction was completed, the palladium on carbon was filtered and the solvent was removed to obtain 14.8 g of product containing 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one (VI). The content of 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one (VI) in the product was 98%, and the yield was 92% (based on 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V)).

[0105] Example 3

[0106] The difference from Example 1 is that 8.4g of sodium hydroxide was added instead of potassium carbonate, while the molar ratio of the raw materials remained unchanged. Etherification and cyclization yielded 14.6g of a product containing 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V). The product contained 97% 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V), and the yield was 85% (based on 2-chloro-4-fluoroacetanilide (II)).

[0107] Example 4

[0108] The difference from Example 1 is that 19.4g of bromine was added instead of chlorine gas, the raw material molar ratio remained unchanged, and acylation and halogenation yielded 23.2g of product containing 2-bromo-4-fluoroacetanilide (II). The content of 2-bromo-4-fluoroacetanilide (II) in the product was 98%, and the yield was 98% (based on 4-fluoroaniline (I)).

[0109] Example 5

[0110] The difference from Example 1 is that 9.2 g of glycolic acid (formula (VII)) was added, the molar ratio of the raw materials remained unchanged, and etherification cyclization was performed to obtain 14.7 g of 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V) product. The content of 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V) in the product was 98%, and the yield was 91% (based on 2-chloro-4-fluoroacetanilide (II)).

[0111] Example 6

[0112] The difference from Example 1 is that 9.5g of acetyl chloride was added instead of acetic anhydride, while the molar ratio of the raw materials remained unchanged. Acylation and halogenation yielded 18.3g of a product containing 2-chloro-4-fluoroacetanilide (II), with a content of 98% of 2-chloro-4-fluoroacetanilide (II) and a yield of 96% (based on 4-fluoroaniline (I)).

[0113] Example 7

[0114] The difference from Example 2 is that 8.6g of sodium hydroxide was added instead of potassium carbonate, while the molar ratio of the raw materials remained unchanged. Etherification cyclization yielded 14.1g of a product containing 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V). The product contained 97% 7-fluoro-2H-1,4-benzoxazine-3(4H)-one (V), and the yield was 85% (based on 2-chloro-4-fluoroacetanilide (II)).

[0115] Examples 1, 3, and 4-6 above are prepared according to process A provided by this invention, and Examples 2 and 7 are prepared according to process B provided by this invention. As can be seen from the above examples, this invention uses 4-fluoroaniline as a raw material to prepare 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one through acylation halogenation, etherification cyclization, and nitration hydrogenation. This solves the problems of significant phenol isomerization and equipment corrosion caused by byproducts in the preparation of 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one in existing technologies, and achieves no isomerization side reaction during the etherification reaction, providing a green and environmentally friendly preparation process for 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one.

[0116] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one, wherein, The preparation method includes: (1) The compound shown in formula (I) is subjected to a first acylation reaction with a first acylation reagent, and then a first halogenation reaction is carried out with a first halogenation reagent to obtain the compound shown in formula (II); (2) In the presence of a polar solvent, a first catalyst and a first acid-binding agent, the compound shown in formula (II) and the compound shown in formula (VII) undergo a first etherification reaction to obtain the compound shown in formula (IV); under cyclization conditions, the compound shown in formula (IV) undergoes a first cyclization reaction to obtain the compound shown in formula (V). (3) The compound shown in formula (V) was subjected to nitration and hydrogenation to obtain 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one shown in formula (VI); Equation (Ⅰ), Formula (II), Equation (Ⅳ), Formula (V), Formula (VI), （Ⅶ）； Where X is Cl, Br or I, R1 is -OCH3, -OH or -NH2, and R is a hydroxyl group or a halogen; The first acylating agent is selected from acetic anhydride or acetyl chloride; The first halogenating agent is selected from at least one of sodium bromate and hydrogen peroxide combination, chlorine, sulfonyl chloride, thionyl chloride, N-chlorosuccinimide, dichlorohydantoin, dibromohydantoin, N-bromosuccinimide and bromine; The first acid-binding agent is selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, pyridine, triethylamine, tetramethylethylenediamine, dimethylpropylenediamine, tetramethylpropylenediamine, N,N'-dimethylethylenediamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, N,N-dimethylaniline, and diisopropylethylamine; The first catalyst is a copper salt; the copper salt is selected from at least one of cuprous chloride, cuprous iodide and cuprous bromide; The polar solvent is selected from solvent A, or a combination of solvent A and solvent B, wherein solvent A is selected from at least one of methanol, ethanol, n-butanol, isopropanol, tert-butanol and water, and solvent B is selected from at least one of N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

2. The production method according to claim 1, wherein In step (1), the conditions for the first acylation reaction include: the first acylation temperature is 30-70℃; the first acylation time is 1-6h; And / or, the molar ratio of the first acylation reagent to the compound shown in formula (I) is 1-1.5:

1.

3. The production method according to claim 2, wherein, In step (1), the conditions for the first acylation reaction include: the first acylation temperature is 30-60℃; the first acylation time is 3-4h; And / or, the molar ratio of the first acylation reagent to the compound shown in formula (I) is 1.1-1.3:

1.

4. The production method according to claim 1, wherein In step (1), the conditions for the first halogenation reaction include: the first halogenation temperature is 0-60℃; the first halogenation time is 1-6h; And / or, the first halogenating agent is chlorine or bromine; And / or, the molar ratio of the first halogenating agent to the compound shown in formula (I) is 1-3:

1.

5. The preparation method according to claim 4, wherein, In step (1), the conditions for the first halogenation reaction include: chlorination temperature of 40-50℃, bromination temperature of 5-15℃, and first halogenation time of 3-4h; And / or, the molar ratio of the first halogenating agent to the compound shown in formula (I) is 1.1-1.3:

1.

6. The preparation method according to claim 1, wherein, In step (2), the compound represented by formula (VII) is selected from at least one of methyl haloacetate, glycolic acid, methyl glycolate and hydroxyacetamide; And / or, the molar ratio of the compound shown in formula (II) to the compound shown in formula (VII) is 1:1-2.

7. The preparation method according to claim 6, wherein, In step (2), the compound represented by formula (VII) is selected from methyl chloroacetate or glycolic acid; And / or, the molar ratio of the compound shown in formula (II) to the compound shown in formula (VII) is 1:1.1-1.

3.

8. The production method according to claim 1, wherein In step (2), the first acid-binding agent is potassium carbonate and / or sodium hydroxide; And / or, the molar ratio of the compound shown in formula (II) to the first acid-binding agent is 1:2-4.

9. The production method according to claim 8, wherein In step (2), the molar ratio of the compound shown in formula (II) to the first acid-binding agent is 1:2.2-2.

4.

10. The production method according to claim 1, wherein, The copper salt is cuprous chloride.

11. The preparation method according to claim 1, wherein, In step (2), the conditions for the first etherification reaction include: the first etherification temperature is 30-200℃; the first etherification time is 4-15h.

12. The preparation method according to claim 11, wherein, In step (2), the conditions for the first etherification reaction include: the first etherification temperature is 70-150℃; the first etherification time is 9-10h.

13. The preparation method according to claim 1, wherein, In step (2), the first cyclization reaction includes adding an acid to the product obtained from the first etherification reaction and reacting it with the compound shown in formula (Ⅳ).

14. The production method according to claim 13, wherein The acid is selected from at least one of sulfuric acid, hydrochloric acid, or phosphoric acid.

15. The preparation method according to claim 14, wherein, The acid is hydrochloric acid.

16. The preparation method according to claim 1 or 13, wherein, The conditions for the first cyclization reaction include: a first cyclization temperature of 90-110℃ and a first cyclization reaction time of 5-6h.

17. The method of producing according to claim 1, wherein, The polar solvent is N,N-dimethylformamide and water.

18. The method of producing according to claim 1, wherein, In step (3), the conditions for the nitration reaction include: nitration temperature of 10-70℃; nitration time of 2-6h; And / or, a nitrifying agent is added to the nitration reaction, wherein the nitrifying agent is concentrated sulfuric acid and concentrated nitric acid.

19. The method of making according to claim 18, wherein, In step (3), the conditions for the nitration reaction include: nitration temperature of 20-40℃ and nitration time of 3-4h.

20. The method of making according to claim 18, wherein, The mass ratio of the concentrated sulfuric acid to the compound shown in formula (V) is 3-5:1; And / or, the molar ratio of the concentrated nitric acid to the compound shown in formula (V) is 1-1.5:

1.

21. The method of making according to claim 20, wherein, The mass ratio of the concentrated sulfuric acid to the compound shown in formula (V) is 3-4:1; And / or, the molar ratio of the concentrated nitric acid to the compound shown in formula (V) is 1.1-1.2:

1.

22. The preparation method according to claim 1, wherein, In step (3), the hydrogenation reaction is carried out in the presence of a hydrogenation catalyst; And / or, the conditions for the hydrogenation reaction include: a hydrogenation temperature of 30-100°C; and a hydrogen pressure of 1-3 MPa.

23. The method of making according to claim 22, wherein, In step (3), the conditions for the hydrogenation reaction include: hydrogenation temperature of 40-60℃ and hydrogen pressure of 1.5-1.8MPa.

24. The method of making according to claim 22, wherein, The hydrogenation catalyst is selected from palladium on carbon or Raney nickel.

25. The preparation method according to claim 24, wherein, The hydrogenation catalyst is palladium on carbon.

26. The method of manufacturing according to claim 24 or 25, wherein, Based on the total amount of palladium on carbon, the palladium content in the palladium on carbon is 5 wt%.

27. The preparation method according to claim 26, wherein, The mass ratio of palladium to the compound shown in formula (V) is 0.02-0.05:

1.

28. A method for preparing 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one, wherein, The preparation method includes: (i) The compound shown in formula (I) is subjected to a second acylation reaction with a second acylation reagent, and then a second halogenation reaction is carried out with a second halogenation reagent to obtain the compound shown in formula (III); (ii) In the presence of a polar solvent, a second catalyst and a second acid-binding agent, the compound shown in formula (Ⅲ) is subjected to a second etherification cyclization reaction to directly obtain the compound shown in formula (V); (iii) The compound shown in formula (V) is subjected to nitration and hydrogenation to obtain 7-fluoro-6-amino-2H-1,4-benzoxazine-3(4H)-one shown in formula (VI); Formula (I), Formula (III), Formula (V), Formula (VI); Where X is Cl, Br or I, and R2 is a halogen; The second acylating agent is selected from haloacetyl chloride; The second halogenating agent is selected from at least one of the following: sodium bromate and hydrogen peroxide combination, chlorine, sulfonyl chloride, thionyl chloride, N-chlorosuccinimide, dichlorohydantoin, dibromohydantoin, N-bromosuccinimide, and bromine; The second acid-binding agent is selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, pyridine, triethylamine, tetramethylethylenediamine, dimethylpropylenediamine, tetramethylpropylenediamine, N,N'-dimethylethylenediamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, N,N-dimethylaniline, and diisopropylethylamine; The second catalyst is a copper salt; the copper salt is selected from at least one of cuprous chloride, cuprous iodide and cuprous bromide; The polar solvent is selected from solvent A, or a combination of solvent A and solvent B, wherein solvent A is selected from at least one of methanol, ethanol, n-butanol, isopropanol, tert-butanol and water, and solvent B is selected from at least one of N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

29. The method of making according to claim 28, wherein, R2 is either Cl or Br.

30. The method of manufacturing according to claim 28, wherein, In step (i), the conditions for the second acylation reaction include: a second acylation temperature of 30-70°C; and a second acylation time of 1-6 h. And / or, the second acylation agent is chloroacetyl chloride; And / or, the molar ratio of the second acylation reagent to the compound shown in formula (I) is 1-1.5:

1.

31. The preparation method according to claim 30, wherein, In step (i), the conditions for the second acylation reaction include: a second acylation temperature of 30-60°C and a second acylation time of 3-4 h; And / or, the molar ratio of the second acylation reagent to the compound shown in formula (I) is 1.1-1.3:

1.

32. The preparation method according to claim 28, wherein, In step (i), the conditions for the second halogenation reaction include: a second halogenation temperature of 0-60°C and a second halogenation time of 1-6 h; And / or, the second halogenating agent is chlorine or bromine; And / or, the molar ratio of the second halogenating agent to the compound shown in formula (I) is 1-3:

1.

33. The preparation method according to claim 32, wherein, In step (i), the conditions for the second halogenation reaction include: chlorination temperature of 40-50℃, bromination temperature of 5-15℃, and second halogenation time of 3-4h; And / or, the molar ratio of the second halogenating agent to the compound shown in formula (I) is 1.1-1.3:

1.

34. The method of manufacturing according to claim 28, wherein, In step (ii), the second acid-binding agent is potassium carbonate and / or sodium hydroxide; And / or, the molar ratio of the compound shown in formula (III) to the second acid-binding agent is 1:1-3.

35. The method of manufacturing according to claim 34, wherein, In step (ii), the molar ratio of the compound shown in formula (Ⅲ) to the second acid-binding agent is 1:2.1-2.

3.

36. The preparation method according to claim 28, wherein, The copper salt is cuprous chloride.

37. The preparation method according to claim 28, wherein, In step (ii), the conditions for the second etherification cyclization reaction include: an etherification cyclization temperature of 40-180℃ and an etherification cyclization time of 1-6h.

38. The preparation method according to claim 37, wherein, In step (ii), the conditions for the second etherification cyclization reaction include: an etherification cyclization temperature of 60-120℃ and an etherification cyclization time of 3-4h.

39. The method of manufacturing according to claim 28, wherein, In step (iii), the polar solvent is N,N-dimethylformamide and water.

40. The preparation method according to claim 28, wherein, In step (iii), the conditions for the nitration reaction include: a nitration temperature of 10-70℃ and a nitration time of 2-6 hours; And / or, a nitrifying agent is added to the nitration reaction, wherein the nitrifying agent is concentrated sulfuric acid and concentrated nitric acid.

41. The method of manufacturing according to claim 40, wherein, In step (iii), the conditions for the nitration reaction include: a nitration temperature of 20-40℃ and a nitration time of 3-4h.

42. The method of manufacturing according to claim 40, wherein, The mass ratio of the concentrated sulfuric acid to the compound shown in formula (V) is 3-5:1; the molar ratio of the concentrated nitric acid to the compound shown in formula (V) is 1-1.5:

1.

43. The method of manufacturing according to claim 42, wherein, The mass ratio of the concentrated sulfuric acid to the compound shown in formula (V) is 3-4:1; the molar ratio of the concentrated nitric acid to the compound shown in formula (V) is 1.1-1.2:

1.

44. The method of manufacturing according to claim 28, wherein, In step (iii), the hydrogenation reaction is carried out in the presence of a hydrogenation catalyst; And / or, the conditions for the hydrogenation reaction include: a hydrogenation temperature of 30-100°C; and a hydrogen pressure of 1-3 MPa.

45. The preparation method according to claim 44, wherein, In step (iii), the conditions for the hydrogenation reaction include: a hydrogenation temperature of 40-60°C and a hydrogen pressure of 1.5-1.8 MPa.

46. The method of manufacturing according to claim 44, wherein, The hydrogenation catalyst is selected from palladium on carbon or Raney nickel.

47. The method of manufacturing according to claim 46, wherein, The hydrogenation catalyst is palladium on carbon.

48. The method of manufacturing according to claim 46 or 47, wherein, Based on the total amount of palladium on carbon, the palladium content in the palladium on carbon is 5 wt%.

49. The method of manufacturing according to claim 48, wherein, The mass ratio of palladium to the compound shown in formula (V) is 0.02-0.05:1.

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