Method for preparing benzoxazinone compound

Abstract

The invention discloses a method for preparing a benzoxazinone compound, which comprises the following steps of: firstly, obtaining a mixed solution of 2-nitro-5-fluorophenol and 3-fluoro-4-nitrophenol from 2, 4-difluoronitrobenzene under the action of alkali, then washing the mixed solution with methylbenzene, removing a methylbenzene layer, regulating the pH value of a water layer to be acidic with acid, and then washing the water layer with methylbenzene to obtain a mixed solution of 2-nitro-5-fluorophenol and 3-fluoro-4-nitrophenol; separating a water layer to obtain a mixture of the 2-nitro-5-fluorophenol and the 3-fluoro-4-nitrophenol; etherifying the obtained mixture and a compound with a structural formula I under the condition of an acid-binding agent to obtain an etherified mixture; reacting the obtained etherified mixture with nitric acid to obtain a nitro compound; then reducing the nitro compound into a diamino compound; compared with a traditional method, the preparation method disclosed by the invention has the advantages that the raw materials are cheap, the reaction conditions are mild, and the safety is high; and the prepared product is high in yield.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and in particular to a method for preparing benzoxazinone compounds. Background Technology

[0002] Benzooxazinones are a valuable class of organic compounds. Many benzooxazinones possess high biological activity and have wide applications in various fields. In pesticide applications, benzooxazinones exhibit herbicidal activity. Therefore, the research and development of benzooxazinones is of great significance. The structure of benzooxazinones is shown in Formula II below:

[0003] When R is H, it is 6-amino-7-fluoro-2H-1,4-benzoxazine-3(4H)-one (IIa), which is an intermediate of propyzamide; when R is F, it is 6-amino-2,2,7-trifluoro-2H-1,4-benzoxazine-3(4H)-one (IIb), which is an intermediate of trifluralin.

[0004]

[0005] BASF Europe's WO2013 / 092858 proposes a method using 5-fluoro-2-nitrophenol as a starting material. This method involves a two-step reduction, resulting in a relatively long route and low yield. The starting material, 5-fluoro-2-nitrophenol, is obtained by the alkaline hydrolysis of 2,4-difluoronitrobenzene. Due to poor selectivity, 10% of 3-fluoro-4-nitrophenol is also produced during hydrolysis. Purification is typically achieved through steam distillation, which is energy-intensive and yields low results. The synthetic route is shown below:

[0006] Zhong Fugui et al. from Shenyang Zhonghua Pesticide Chemical R&D Co., Ltd. proposed a method using m-fluorophenol as a starting material in the journal *Modern Pesticides*, Volume 22, Issue 5, p. 59. However, this method is not economical due to the high price of m-fluorophenol, and it also introduces two nitro groups, requiring a large initial input of nitric acid, which poses certain safety risks. The synthetic route is shown below:

[0007] Chinese invention patent CN108976129A discloses a method of first nitrifying and hydrolyzing 2,4-difluoronitrobenzene, and then reacting it with compound 1 to obtain a dinitro compound. The product can be obtained through a single reduction with a high yield. However, this reaction involves the high-temperature etherification of the dinitro compound, which poses a significant safety risk and is not suitable for industrial production.

[0008] Chinese invention patent CN104628572A discloses the reaction of 2,4-difluoronitrobenzene and glycolic acid ester to generate a mixture, which is then reduced after nitration. Glycolic acid ester is a relatively expensive raw material, and there is no similar intermediate in the synthesis of 6-amino-2,2,7-trifluoro-2H-1,4-benzoxazine-3(4H)-one.

[0009] Therefore, this invention proposes a method for preparing benzoxazinone compounds. Summary of the Invention

[0010] In view of the problems existing in the prior art, the purpose of the present invention is to provide a method for preparing benzoxazinone compounds, which solves the problems of high production cost, many operation steps and complicated process.

[0011] To achieve the above objectives, the technical solution of the present invention is as follows: This invention provides a method for preparing benzoxazinone compounds, comprising the following steps: a. First, 2,4-difluoronitrobenzene is reacted with an alkali to obtain a mixed solution of 2-nitro-5-fluorophenol and 3-fluoro-4-nitrophenol. Then, the mixed solution is washed with toluene, the toluene layer is removed, the pH of the aqueous layer is adjusted to acidic with acid, and the aqueous layer is removed to obtain a mixture of 2-nitro-5-fluorophenol and 3-fluoro-4-nitrophenol. b. Etherify the mixture obtained in step a and the compound having structural formula I under acid-binding conditions to obtain an etherified mixture; c. React the mixture obtained in step b with nitric acid to obtain a dinitro compound; d. Reduce the dinitro compound obtained in step c to a diamino compound; e. Acidify and cyclize the diamino compound obtained in step d to obtain benzoxazinone; The synthetic route is shown below: Where R is H or F; X is Br or Cl; and R1 is methoxy, ethoxy, dimethylamino, diethylamino, methylisopropylamino, tetrahydropyrrolyl or piperidinyl.

[0012] Furthermore, the compound having structural formula I is one of the following: .

[0013] Furthermore, the base in step a is sodium hydroxide or potassium hydroxide; the acid in step a is sulfuric acid or hydrochloric acid.

[0014] Furthermore, in step b, the acid-binding agent is potassium carbonate or sodium carbonate; and in step b, the solvent is DMF or acetonitrile.

[0015] Furthermore, the reaction temperature in step b is from room temperature to 140°C; the molar ratio of the mixture of 2-nitro-5-fluorophenol and 3-fluoro-4-nitrophenol to structural formula I in step b is 0.8~1.2:1.

[0016] Furthermore, the amount of nitric acid used in step c is 1.0 to 1.2 of the molar amount of the mixture; the solvent in step c is sulfuric acid; and the reaction temperature in step c is 10-60℃.

[0017] Furthermore, the catalyst in step d is Raney nickel, palladium on carbon, or platinum on carbon; the pressure in step d is 0.1-2.0 MPa; and the reaction temperature in step d is 20-80 °C.

[0018] Furthermore, the reaction temperature in step e is 20-80℃; the acid used in step e is sulfuric acid or hydrochloric acid.

[0019] Further, step d involves reduction using an acid system with iron powder or zinc powder.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows: 1) The hydrolyzed mixture in step a of this invention can be used directly, eliminating the need for post-processing and increasing the utilization rate of carbon atoms; the nitration in step c can convert the mixture into the desired structure. 2) Compared with traditional methods, the preparation method of the present invention uses inexpensive raw materials, mild reaction conditions, and is highly safe; the yield of the prepared product is high. Attached Figure Description

[0021] Figure 1 Liquid phase diagram of the hydrolysis products of 2,4-difluoronitrobenzene;

[0022] Figure 2 NMR spectrum of the hydrolysis products of 2,4-difluoronitrobenzene; Figure 3 Liquid phase diagrams of the main product and isomers in Example 5; Figure 4 The liquid phase diagrams are of the main product and isomers in Example 7. Detailed Implementation

[0023] The present invention will be further described below with reference to embodiments, but the scope of protection of the present invention is not limited to the scope described.

[0024] Example 1

[0025] 62.6 g (0.4 mol) of 2,4-difluoronitrobenzene and 220 ml of water were added to the reactor at room temperature. 150 g of 50% potassium hydroxide solution was added dropwise. The reaction system was kept at 40 °C and reacted for 4 hours. The reaction solution was washed with toluene. The pH of the aqueous layer was adjusted to 3.0 with sulfuric acid. The organic layer was separated at 40 °C and washed once with water to obtain 59.6 g of the reaction mixture (yield 94.9%, of which 2-nitro-5-fluorophenol mass fraction was 90.3% (retention time 8.05 min) and 3-fluoro-4-nitrophenol mass fraction was 9.7% (retention time 5.269 min). NMR: 6.28 0.11 H, 6.7-6.75 1.3 H, 6.83-6.86 1 H, 8.03-8.06 0.15 H, 8.15-8.18 1 H, 10.81 1 H).

[0026] Example 2 62.6 g (0.4 mol) of 2,4-difluoronitrobenzene and 220 ml of water were added to the reactor at room temperature. 180 g of 30% sodium hydroxide solution was added dropwise. The reaction system was kept at 40 °C and reacted for 4 hours. The reaction solution was washed with toluene. The pH of the aqueous layer was adjusted to 3.0 with hydrochloric acid. The organic layer was separated at 40 °C and washed once with water to obtain 56.3 g of the reaction mixture (yield 89.6%).

[0027] The liquid phase results of the hydrolysis products of 2,4-difluoronitrobenzene are shown below:

[0028] Example 3

[0029] At room temperature, 47.1 g (0.3 mol) of the mixture obtained in Example 1, 220 ml of DMF, and 62.2 g of solid potassium carbonate were added to the reactor. The temperature was raised to 50 °C, and 35.8 g (0.33 mol) of methyl chloroacetate was added dropwise. After the addition was complete, the temperature was maintained for 4 hours. The potassium carbonate was removed by filtration. The yellow solid obtained by adding water after concentrating the reaction solution was dried to obtain 63.9 g (yield of 92.9%).

[0030] Example 4

[0031] At room temperature, 47.1 g (0.3 mol) of the mixture obtained in Example 2, 220 ml of DMF, and 62.2 g of solid sodium carbonate were added to the reactor. The temperature was raised to 50 °C, and 40.4 g (0.33 mol) of ethyl chloroacetate was added dropwise. After the addition was complete, the temperature was maintained for 4 hours. The sodium carbonate was filtered off, and the yellow solid obtained after the reaction solution was concentrated and water was added was dried to obtain 61.7 g (yield of 84.6%).

[0032] Example 5 (Ib-4) is 2-bromo-N,N-diethyl-2,2-difluoroacetamide. At room temperature, 47.1 g (0.3 mol) of the mixture obtained in Example 1, 220 ml of DMF, and 62.2 g of solid potassium carbonate were added to the reactor. The temperature was raised to 50 °C, and 62.1 g (0.27 mol) of (Ib-4) was added dropwise. After the addition was complete, the temperature was raised to 95 °C. Two main peaks were generated under controlled conditions: the peak eluted at 19.198 min with a content of 68.325% (major product), and the peak eluted at 20.625 min with a content of 6.28% (minor product). The chromatogram is attached. Figure 3 After the reaction was completed, potassium carbonate was removed by filtration. The reaction solution was concentrated to obtain an oily substance, 84.4 g (yield of 91.9%), with a ratio of main product to isomer (91.05:8.9).

[0033] Figure 3 The analysis results are as follows:

[0034] Example 6 (Ib-7) is 2-bromo-2,2-difluoro-1-morpholinoethyl ketone. At room temperature, 47.1 g (0.3 mol) of the mixture obtained in Example 1, 220 ml of DMF, and 62.2 g of solid potassium carbonate were added to the reactor. The temperature was raised to 50 °C, and 65.9 g (0.27 mol) of (Ib-7) was added dropwise. After the addition was complete, the temperature was raised to 100 °C. After the reaction was completed under central control, the potassium carbonate was filtered off. The reaction solution was concentrated to obtain an oily substance of 88.7 g (yield of 92.3%).

[0035] Example 7 (Ib-6) is 2-bromo-2,2-difluoro-1-tetrahydropyrrolidone. At room temperature, 47.1 g (0.3 mol) of the mixture obtained in Example 1, 220 ml of DMF, and 62.2 g of solid potassium carbonate were added to the reactor. The temperature was raised to 50 °C, and 61.6 g (0.27 mol) of (Ib-6) was added dropwise. After the addition was complete, the temperature was raised to 100 °C. After the reaction was completed under intermediate control, two major peaks were generated: one with a peak time of 13.417 min and a content of 80.52% (major product), and the other with a peak time of 14.18 min and a content of 5.51% (minor product). The chromatogram is attached. Figure 4 After filtering to remove potassium carbonate, the reaction solution was concentrated to obtain an oily substance, 78.1 g (yield 95.1%).

[0036] Figure 4 The analysis results are as follows:

[0037] Example 8 Add 300 ml of concentrated sulfuric acid to the reactor, and slowly add 57.3 g (0.25 mol) of the mixture obtained in Example 3 while cooling. Stir for 1 hour, and add 17.3 g (0.275 mol) of concentrated nitric acid dropwise at 20 °C. Keep the mixture at this temperature for 4 hours. After the reaction is complete, quench the reaction solution in water, filter to obtain a yellow solid, and dry to obtain 66.0 g of methyl [(5-fluoro-2,4-dinitrophenyl)oxy]acetate (yield 96.3%).

[0038] Example 9 Add 300 ml of concentrated sulfuric acid to the reactor, and slowly add 61.2 g (0.20 mol) of the mixture obtained in Example 5 while cooling. Stir for 1 hour, and add 13.9 g (0.275 mol) of concentrated nitric acid dropwise at 20 °C. Keep the mixture at this temperature for 4 hours. After the reaction is complete, quench the reaction solution in water, filter to obtain a yellow solid, and dry to obtain 53.6 g of N,N-diethyl-2,2-difluoro-2-[(5-fluoro-2,4-dinitrophenyl)oxy]acetamide (yield 85.0%).

[0039] Example 10 Add 300 ml of concentrated sulfuric acid to the reactor, and slowly add 64.0 g (0.20 mol) of the mixture obtained in Example 6 while cooling. Stir for 1 hour, add 13.9 g (0.275 mol) of concentrated nitric acid dropwise at 20 °C, raise the temperature to 40 °C, and keep it at that temperature for 6 hours. After the reaction is complete, quench the reaction solution in water, filter and dry to obtain 62.3 g of 2,2-difluoro-2-[(5-fluoro-2,4-dinitrophenyl)oxy]-1-(morpholino-1)-acetone (yield 85.3%).

[0040] Example 11 Add 300 ml of concentrated sulfuric acid to the reactor, and slowly add 60.8 g (0.20 mol) of the mixture obtained in Example 7 while cooling. Stir for 1 hour, and add 13.9 g (0.275 mol) of concentrated nitric acid dropwise at 20 °C. Keep the mixture at this temperature for 12 hours. After the reaction is complete, quench the reaction solution in water, filter to obtain a yellow solid, and dry to obtain 66.4 g of 2,2-difluoro-2-[(5-fluoro-2,4-dinitrophenyl)oxy]-1-(tetrahydropyrrol-1)-acetone (yield 95.1%).

[0041] Example 12 In a high-pressure reactor, 137.1 g (0.5 mol) of methyl acetate [(5-fluoro-2,4-dinitrophenyl)oxy]acetate obtained in Example 8, 800 ml of methanol, and 10 g of Raney nickel were added. The reactor was sealed, purged, and kept at 20-30 °C. Hydrogenation was carried out at 1.0-1.5 MPa until the reaction was complete. The catalyst was removed by filtration. 200 ml of concentrated hydrochloric acid was added, and the reactor was kept at 50 °C for one hour. The mixture was adjusted to neutral with sodium hydroxide solution, concentrated to remove methanol, and water was added to precipitate the solid, yielding 72.4 g of 6-amino-7-fluoro-2H-1,4-benzoxazine-3(4H)-one (yield 79.5%).

[0042] Example 13 In a high-pressure reactor, 175.6 g (0.5 mol) of N,N-diethyl-2,2-difluoro-2-[(5-fluoro-2,4-dinitrophenyl)oxy]acetamide obtained in Example 9, 800 ml of methanol, and 5 g of 10% palladium on carbon were added. The reactor was sealed, and after displacement, it was kept at 20-30 °C. Hydrogenation was carried out at 1.0-1.5 MPa until the reaction was complete. The catalyst was removed by suction filtration, and 200 ml of concentrated hydrochloric acid was added. The reactor was kept at 50 °C for one hour. The solution was adjusted to neutral with sodium hydroxide solution, concentrated to remove methanol, and water was added to precipitate the solid. The solid was dried to obtain 92.7 g of 6-amino-2,2,7-trifluoro-2H-1,4-benzoxazine-3(4H)-one (yield 85.0%).

[0043] Example 14 In a high-pressure reactor, 182.6 g (0.5 mol) of the sample obtained in Example 10, 800 ml of methanol, and 10 g of 5% palladium on carbon were added. The reactor was sealed and purged. After replacement, the mixture was kept at 20-30 °C and hydrogenated at 1.0-1.5 MPa until the reaction was complete. The catalyst was removed by vacuum filtration. 200 ml of concentrated hydrochloric acid was added, and the mixture was kept at 50 °C for one hour. The mixture was adjusted to neutral with sodium hydroxide solution, concentrated to remove methanol, and water was added to precipitate the solid, yielding 97.1 g of dried 6-amino-2,2,7-trifluoro-2H-1,4-benzoxazine-3(4H)-one (yield 89.0%).

[0044] Example 15 In a high-pressure reactor, 174.6 g (0.5 mol) of the sample obtained in Example 11, 800 ml of methanol, and 15 g of 3% platinum carbon were added. The reactor was sealed and purged. After replacement, the mixture was kept at 20-30 °C and hydrogenated at 1.0-1.5 MPa until the reaction was complete. The catalyst was removed by vacuum filtration. 200 ml of concentrated hydrochloric acid was added, and the mixture was kept at 50 °C for one hour. The mixture was adjusted to neutral with sodium hydroxide solution, concentrated to remove methanol, and water was added to precipitate the solid, yielding 103.3 g of dried 6-amino-2,2,7-trifluoro-2H-1,4-benzoxazine-3(4H)-one (yield 94.7%).

[0045] Example 16 137.1 g (0.5 mol) of methyl acetate [(5-fluoro-2,4-dinitrophenyl)oxy]acetate obtained in Example 8 was added to 2000 ml of 10% hydrochloric acid. 280 g (5.0 mol) of iron powder was added in batches while stirring. After the reaction was complete, the iron sludge was filtered out. The mother liquor was adjusted to neutral with alkali and filtered to obtain a brown solid. The solid was slurried with methanol to obtain 125.4 g of 6-yl-7-fluoro-2H-1,4-benzoxazine-3(4H)-one (yield 57.5%).

Claims

1. A method for preparing benzoxazinone compounds, characterized in that... Includes the following steps: a. First, 2,4-difluoronitrobenzene is reacted with an alkali to obtain a mixed solution of 2-nitro-5-fluorophenol and 3-fluoro-4-nitrophenol. Then, the mixed solution is washed with toluene, the toluene layer is removed, the pH of the aqueous layer is adjusted to acidic with acid, and the aqueous layer is removed to obtain a mixture of 2-nitro-5-fluorophenol and 3-fluoro-4-nitrophenol. b. Etherify the mixture obtained in step a and the compound having structural formula I under acid-binding conditions to obtain an etherified mixture; c. React the mixture obtained in step b with nitric acid to obtain a dinitro compound; d. Reduce the dinitro compound obtained in step c to a diamino compound; e. Acidify and cyclize the diamino compound obtained in step d to obtain benzoxazinone; The synthetic route is shown below: Where R is H or F; X is Br or Cl; and R1 is methoxy, ethoxy, dimethylamino, diethylamino, methylisopropylamino, tetrahydropyrrolyl or piperidinyl.

2. The method for preparing benzoxazinone compounds according to claim 1, characterized in that... One of the compounds having structural formula I is as follows: 。 3. The method for preparing benzoxazinone compounds according to claim 1, characterized in that... The base in step a is sodium hydroxide or potassium hydroxide; the acid in step a is sulfuric acid or hydrochloric acid.

4. The method for preparing benzoxazinone compounds according to claim 1, characterized in that... In step b, the acid-binding agent is potassium carbonate or sodium carbonate; the solvent in step b is DMF or acetonitrile.

5. The method for preparing benzoxazinone compounds according to claim 1, characterized in that... In step b, the reaction temperature is from room temperature to 140°C; in step b, the molar ratio of the mixture of 2-nitro-5-fluorophenol and 3-fluoro-4-nitrophenol to structural formula I is 0.8~1.2:

1.

6. The method for preparing benzoxazinone compounds according to claim 1, characterized in that... The amount of nitric acid used in step c is 1.0 to 1.2 of the molar amount of the mixture; the solvent in step c is sulfuric acid; the reaction temperature in step c is 10-60℃.

7. The method for preparing benzoxazinone compounds according to claim 1, characterized in that... The catalyst in step d is Raney nickel, palladium on carbon, or platinum on carbon; the pressure in step d is 0.1-2.0 MPa; and the reaction temperature in step d is 20-80℃.

8. The method for preparing benzoxazinone compounds according to claim 1, characterized in that... The reaction temperature in step e is 20-80℃; the acid used in step e is sulfuric acid or hydrochloric acid.

9. The method for preparing benzoxazinone compounds according to claim 1, characterized in that... Step d involves reduction using an acid system with iron powder or zinc powder.

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