CN116082325A - Benzoxazinone compounds containing isoxazole heterocycles and their preparation methods and applications - Google Patents

Abstract

式（I）中苯环上的取代基R数量为1~2个，取代基R为氢、C1~C4烷基、三氟甲基、C1~C4烷氧基或卤素。本发明所得产物的结构经核磁氢谱进行了确认，并对所得的20个目标产物进行了除草活性测试，结果表明：I‑1~I‑20化合物无论是对双子叶油菜的胚根还是单子叶小麦的茎，均能表现出一定的抑制作用，且对小麦茎的抑制效果明显优于对油菜的胚根。The invention discloses a benzoxazinone compound containing an isoxazole heterocycle and its preparation method and application. The structural formula of the benzoxazinone compound containing an isoxazole heterocycle is shown in formula (I) :

The number of substituents R on the benzene ring in formula (I) is 1-2, and the substituents R are hydrogen, C1-C4 alkyl, trifluoromethyl, C1-C4 alkoxy or halogen. The structure of the product obtained in the present invention has been confirmed by proton nuclear magnetic spectrum, and the herbicidal activity test has been carried out to 20 target products of gained, and the result shows: No matter I‑1～I‑20 compound is to the radicle of dicotyledonous rapeseed or monad The stems of leaf wheat can all show a certain inhibitory effect, and the inhibitory effect on wheat stems is obviously better than that on rapeseed radicles.

Description

Benzoxazinone compounds containing isoxazole heterocycles and preparation methods and applications thereof

Technical Field

The invention belongs to the technical field of chemical synthesis and drug application, and specifically relates to a benzoxazinone compound containing an isoxazole heterocycle, and a preparation method and application thereof.

Background Art

Due to the large-scale and continuous use of herbicides by humans, weed resistance genes have mutated, and the number of weed species with significant resistance to the above inhibitors has continued to rise. Weed resistance has become a major problem in weed control. In order to stabilize food production in agricultural production, it is necessary to develop new herbicides to replace the previously resistant herbicides. In recent decades, PPO inhibitors have been the fastest-growing highly active herbicides with target resistance, so their research and development prospects are very broad. In the process of herbicide research and development, PPO inhibitors with strong broad-spectrum and novel structures will be the trend of herbicide development at home and abroad in the future.

Summary of the invention

The purpose of the present invention is to provide a benzoxazinone compound containing an isoxazole heterocycle, and a preparation method and application thereof. In order to study greener and less toxic safe pesticides, the present invention uses fluazifop-butyl as a lead compound, introduces an isoxazole heterocycle by 1,3-dipolar cyclization with its alkynyl group, and designs and synthesizes a benzoxazinone compound containing an isoxazole heterocycle.

The benzoxazinone compound containing isoxazole heterocycle has a structural formula as shown in formula (I):

In formula (I), the number of substituents R on the benzene ring is 1 to 2, and the substituents R are hydrogen, C1 to C4 alkyl, trifluoromethyl, C1 to C4 alkoxy or halogen.

Preferably, the substituent R on the benzene ring in formula (I) is 2,4-dichloro, p-fluoro, p-methyl, m-methyl, p-trifluoromethyl, o-methoxy, p-bromo, o-bromo, 3,5-dimethyl, p-ethoxy, hydrogen, p-isobutyl, p-isopropoxy, p-tert-butyl, p-isopropyl, p-chloro, p-ethyl, 2,3-dimethyl, m-fluoro or m-phenoxy.

The method for preparing the benzoxazinone compound containing isoxazole heterocycle comprises the following steps:

1) Using 2,4-difluoronitrobenzene as a raw material, reacting with sodium hydroxide in a water solvent to generate 5-fluoro-2-nitrophenol;

2) Using DMF as solvent and 5-fluoro-2-nitrophenol as raw material, reacting with ethyl bromoacetate in the presence of potassium carbonate to generate a compound as shown in formula (II);

3) using compound (II) as a raw material, reacting with reduced iron powder and glacial acetic acid to generate a compound as shown in formula (III);

4) using compound (III) as a raw material, reacting with concentrated nitric acid and concentrated sulfuric acid to generate a compound as shown in formula (IV);

5) using DMF as solvent and compound (IV) as raw material, reacting with propyne bromide in the presence of cesium carbonate to generate a compound represented by formula (V);

6) using a methanol-water mixture with a volume ratio of 1 to 4:1 as a solvent, using compound (VI) as a raw material, reacting with hydroxylamine hydrochloride and potassium carbonate to generate a compound represented by formula (VII);

7) using dichloromethane as solvent and compound (VII) as raw material to react with NCS, and directly adding triethylamine and compound (V) obtained in step 5) after the reaction to generate a benzoxazinone compound containing an isoxazole heterocycle as shown in formula (I);

The substituent R in formula (VI) and formula (VII) is the same as in formula (I).

The reaction process is as follows:

Furthermore, when synthesizing 5-fluoro-2-nitrophenol in step 1), the reaction temperature is 50-60° C., the reaction time is 6-8 h, and the molar ratio of 2,4-difluoronitrobenzene to sodium hydroxide is 1:2-4.

Furthermore, in step 2), when synthesizing the compound represented by formula (II), the molar ratio of 5-fluoro-2-nitrophenol, potassium carbonate and ethyl bromoacetate is 1:1.2-1.3:1.05-1.1.

Furthermore, when synthesizing the compound shown in formula (III) in step 3), the reaction time is 4-6h, the reaction temperature is 75-85°C, the molar ratio of the compound (II) to the reduced iron powder is 1:1.5-2.5, and the concentration of the compound (II) in glacial acetic acid is 0.45-0.5 mol/L.

Furthermore, when the compound represented by formula (IV) is synthesized in step 4), the molar ratio of the compound represented by formula (III) to concentrated nitric acid is 1:1.5-4, the mass fraction of the concentrated sulfuric acid is 75-85%, and the concentration of the compound represented by formula (III) in concentrated sulfuric acid is 0.1-0.15 mol/L.

Furthermore, when synthesizing the compound represented by formula (V) in step 5), the molar ratio of the compound represented by formula (IV) to propyne bromide is 1:1.05-1.3, and the molar ratio of the compound represented by formula (IV) to cesium carbonate is 1:1.2-1.3.

Furthermore, in step 6), when synthesizing the compound represented by formula (VII), the molar ratio of the compound represented by formula (VI), potassium carbonate and hydroxylamine hydrochloride is 1:1.2-1.3:1.2-1.3.

Furthermore, in step 7), when synthesizing the benzoxazinone compound containing an isoxazole heterocycle, the molar ratio of the compound represented by formula (VII), NCS, triethylamine and the compound represented by formula (V) is 1:1.2-1.3:1.2-1.4:1.1-1.2.

Application of the above-mentioned benzoxazinone compounds containing isoxazole heterocycles in the preparation of herbicides.

The beneficial effects of the present invention are:

The structure of the product obtained by the present invention is confirmed by nuclear magnetic hydrogen spectrum, and the herbicidal activity test is carried out on the obtained 20 target products, and the results show that all compounds can show a certain inhibitory effect, and the inhibitory effect on wheat stems is significantly better than that on rapeseed radicles. At a concentration of 100ppm, the inhibition rate of I-16 on rapeseed radicles is 82.6%, and the inhibition rates of I-3, I-8, I-11, I-18 and I-20 can all reach more than 70%; the inhibitory effect of I-1, I-8, I-11 and I-14, I-16 and I-18 on wheat stems can all reach 100%, and when the concentration is reduced to a concentration of 10ppm, the inhibition rates of I-1 and I-16 on wheat stems can still reach about 90%.

DETAILED DESCRIPTION

The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

Example 1

1) Preparation of 5-fluoro-2-nitrophenol

Add 2,4-difluoronitrobenzene (100.00 mmol) and 10 mL of water to a 100 mL round-bottomed reaction bottle, heat the reaction system to 55°C, slowly add 40.00 g of 30% sodium hydroxide aqueous solution while stirring, and continue stirring at 55°C for 6 hours after the addition is completed for about 15 minutes. After the reaction is completed, cool the reaction solution to room temperature, then add dilute hydrochloric acid to the reaction solution to adjust the pH to 2, and finally extract it three times with 60 mL of dichloromethane, combine the organic phases, and remove the dichloromethane solvent by vacuum rotary evaporation to obtain 10.70 g of crude 5-fluoro-2-nitrophenol, which is directly used in the next step without purification. Yield: 68%, yellow solid, melting point: 32-33°C.

2) Preparation of the compound represented by formula (II)

5-Fluoro-2-nitrophenol (51.08 mmol) and potassium carbonate (63.87 mmol) were weighed and added to a 100 mL round-bottom reaction bottle, and 60 mL of DMF solution was added to dissolve it. The mixture was stirred at room temperature for about 15 min, and then ethyl bromoacetate (53.66 mmol) was slowly added dropwise. The reaction was tracked by TLC (V _EA /V _PE = 1:6). The reaction was completed after about 12 h. The reaction solution was poured into a beaker, and then 50 mL of water and 50 mL of ethyl acetate were added for extraction. After the extraction was completed, the organic layer was washed two to three times with a saturated sodium chloride solution, and the organic phase was dried with anhydrous sodium sulfate. Finally, the ethyl acetate solvent was removed by rotary evaporation under reduced pressure, and then recrystallized with ethanol to obtain 8.84 g of the compound shown in formula (II), which was an oily liquid with a yield of 71.1%.

3) Preparation of the compound represented by formula (III)

The compound represented by formula (II) (29.05 mmol) and 60 mL of glacial acetic acid were added to a 250 mL three-necked round-bottomed reaction bottle and stirred. The reaction system was heated to 80°C and kept in a reflux state. Subsequently, reduced iron powder (58.10 mmol) was weighed and added to the reaction system in three batches within 20 min. TLC (V _EA /V _PE = 1:4) was used to track the reaction. The reaction was completed after about 4 h. The reaction solution was cooled to room temperature and poured into 100 mL of ice water until a large amount of white precipitate was precipitated in the reaction solution. The white precipitate was filtered, washed with water and dried to finally obtain 3.20 g of the compound represented by formula (III), with a yield of 65.9%, a white solid, and a melting point of 203-204°C.

4) Preparation of the compound represented by formula (IV)

The compound represented by formula (III) (10.65 mmol) and 80 mL of a newly prepared 80% concentrated sulfuric acid solution were slowly added to a 250 mL three-necked round-bottom reaction bottle and stirred. An appropriate amount of ice was added to cool the system to 0°C. Subsequently, 1.78 g of 65% nitric acid and 5 mL of 80% concentrated sulfuric acid were dropped into the solution within 10 min. The reaction was tracked and monitored by TLC (V _EA /V _PE = 1:3). After the reaction was completed in about 45 min, the reaction solution was poured into 100 mL of ice water and stirred for 30 min. A large amount of yellow precipitate was precipitated from the system. The yellow precipitate was filtered, washed with water and finally dried to obtain 2.02 g of the compound represented by formula (IV) with a yield of 89.4%. The product was a light yellow solid with a melting point of 207-208°C.

5) Preparation of the compound represented by formula (V)

The compound represented by formula (IV) (7.14 mmol) and anhydrous cesium carbonate (8.93 mmol) were added to a 100 mL round-bottom reaction bottle, and 50 mL of DMF solution was added. After stirring at room temperature for about 15 min, propargyl bromide (7.50 mmol) was slowly added dropwise. After the addition was completed in about 10 min, the mixture was stirred overnight. After the reaction was completed, the reaction solution was poured into a separatory funnel, and then 50 mL of water and 50 mL of ethyl acetate were added for extraction. The organic layer was washed three times with a saturated sodium chloride solution and dried with an appropriate amount of anhydrous sodium sulfate. Finally, the ethyl acetate was dried under reduced pressure and applied to a column for column chromatography. The compound represented by formula (V) was separated and purified with an eluent of V _EA /V _PE = 1:4 to obtain 1.51 g of the compound with a yield of 84.5% as a yellow solid with a melting point of 108-109°C.

6) Preparation of 2,4-dichlorobenzaldehyde oxime

2,4-dichlorobenzaldehyde (2.00 mmol) and 20 mL of methanol were added to a 100 mL reaction bottle, and then anhydrous potassium carbonate (2.50 mmol) and hydroxylamine hydrochloride (2.50 mmol) were dissolved in 10 mL of water, and then added dropwise to the above methanol solution containing 2,4-dichlorobenzaldehyde. The mixture was stirred at room temperature for about 1 h, and the reaction was tracked by TLC. After the reaction, the methanol solvent was dried, 20 mL of water and 40 mL of ethyl acetate were added for extraction, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure with ethyl acetate, and then loaded on a column for column chromatography. 0.35 g of intermediate 2,4-dichlorobenzaldehyde oxime was separated and purified using an eluent of V _EA /V _PE = 1:4, and a white solid was obtained with a melting point of 134-135° C. and a yield of 87.7%.

7) Preparation of compounds I-1 to I-20

Weigh compound (VII) (0.50 mmol) and dissolve it in 20 mL of dichloromethane. Add N-chlorosuccinimide (0.60 mmol) in batches at room temperature. Stir the reaction solution at room temperature for about 2 h. TLC (V _EA /V _PE = 1:4) is used to track and monitor the reaction. After the reaction is completed, no treatment is performed. Then, triethylamine (0.66 mmol) is directly and slowly added dropwise to the above reaction solution. After stirring for about 30 min, the previously prepared key intermediate compound (V) (0.55 mmol) is added and stirred overnight at room temperature. After the reaction is completed, the reaction solution is filtered to remove triethylamine hydrochloride. Finally, the dichloromethane solvent is dried under reduced pressure and loaded onto a column for column chromatography. The eluent with V _EA /V _PE = 1:6 is used for separation and purification to finally obtain the target compound.

式(Ⅵ)和式(Ⅶ)中的取代基R均与目标化合物I-1～I-20的苯环上的取代基相同，并参见表1中，最终所得目标产物的收率以及理化数据汇总于表1中。目标化合物I-1～I-20的氢谱表征数据汇总于表2中。The preparation method of target compounds I-1 to I-20 repeats the above process, the only difference is that "the 2,4-dichlorobenzaldehyde raw material in step 6) is replaced by an equal molar amount of compound (VI)", and the structural formula of compound (VI) is:

The substituents R in formula (VI) and formula (VII) are the same as the substituents on the benzene ring of the target compounds I-1 to I-20, and are shown in Table 1. The yields and physicochemical data of the target products are summarized in Table 1. The hydrogen spectrum characterization data of the target compounds I-1 to I-20 are summarized in Table 2.

Table 1 Physical and chemical data of benzoxazinone compounds containing isoxazole heterocycle

Table 2 Hydrogen spectrum data of benzoxazinone compounds containing isoxazole heterocycle

Example 2 Herbicidal Activity Test

Test methods

(1) Test subjects: seeds of dicotyledonous rapeseed (Brassica napus) and monocotyledonous wheat (Triticum aestivum).

(2) Experimental treatment: Before the biological activity test, the seeds were sterilized by soaking them in a 5%-10% sodium hypochlorite solution for about 10 min for sterilization. After soaking for 5 hours, they were repeatedly rinsed with deionized water from a Millipore ultrapure water system and dried in a sterile environment.

(3) Test method: Weigh 2 mg of the compound to be tested into a 5 mL EP tube, pipette 2 mL of acetone into the tube and shake to completely dissolve the compound to be tested, and prepare a 1 mg/L stock solution for use. Take 1 mL of the stock solution into a 10 mL EP tube and add 9 mL of deionized water to dilute to obtain a 100 ppm test solution. Take 1 mL of the solution in the previous step into a 10 mL EP tube and add 9 mL of deionized water to dilute to obtain a 10 ppm test solution. Take flumioxazin as a control drug.

Wheat biological activity test: Acetone was used as the solvent in the experiment. All biological tests were divided into two replicates and were performed in a cup. Pollution caused by the external environment should be avoided during the experiment. A filter paper with a diameter of 7.5 cm was spread on it, 10 mL of a certain concentration of the test compound solution was added, 10 wheat seeds were sown, and cultured in a natural environment. The height of the wheat seedlings was measured after about a week. The herbicidal activity of the target compound was detected by inhibiting the growth of the wheat seedlings. Activity index: plant height growth inhibition rate (%).

Rapeseed biological activity test: Acetone was used as the solvent in the experiment. All biological tests were divided into two replicates and were performed in sterile pyrogen-free polystyrene 24-well cell culture plates (CoStar 3524, Corning Incorporated). During the experiment, contamination caused by the external environment should be avoided. The above culture plate was placed in a sterile environment and a filter paper disk with a diameter of 1.5 cm was used. After adding 200 μL of the test compound solution to the control well, 5 seeds were placed in all wells, and the sample wells were covered and sealed with raw tape; incubated at room temperature in the dark, and the radicle length was measured after about a week. The activity index was: radicle growth inhibition rate (%).

Inhibition rate calculation:

The activity test results are shown in Table 3:

Table 3 Herbicidal activity of benzoxazinone compounds containing isoxazole heterocycle (i.e. inhibition rate, unit %)

The herbicidal activity results of benzoxazinone compounds containing isoxazole heterocycles (20 compounds) show (Table 3) that compounds I-1 to I-20 can show certain inhibitory effects on both the radicle of dicotyledonous rape and the stem of monocotyledonous wheat, and the inhibitory effect on wheat stem is significantly better than that on rapeseed radicle. At a concentration of 100 ppm, the inhibition rate of I-16 on rapeseed radicle is 82.6%, and the inhibition rates of I-3, I-8, I-11, I-18 and I-20 can all reach more than 70%. Compounds I-1 to I-20 have obvious inhibitory effects on wheat stems, among which I-1, I-8, I-11 and I-14, I-16, and I-18 can all reach 100% of the inhibitory effects on wheat stems. When the concentration is reduced to 10 ppm, the inhibition rates of I-1 and I-16 on wheat stems can still reach about 90%. Comparing the biological activity data of compounds I-1 to I-20 against wheat stems, from a structural point of view, the most active I-1 and I-16 both contain chlorine on the benzene ring. The two chlorine atoms of I-1 are located at the ortho and para positions of the benzene ring. It can be inferred that the introduction of halogen atom chlorine may enhance the inhibitory effect of the compounds on wheat stems. At the same time, it was observed that the introduction of bromine atoms into I-7 and I-8 also had a good inhibitory effect, which indicates that the presence of chlorine atoms or bromine atoms on the benzene ring is conducive to improving the activity.

The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept. The protection scope of the present invention should not be regarded as limited to the specific forms described in the embodiments. The protection scope of the present invention is also limited to the equivalent technical means that can be thought of by those skilled in the art based on the inventive concept.

Claims (10)

1. The benzoxazinone compound containing isoxazole heterocycle is characterized in that the structural formula is shown as formula (I):

the number of the substituent R on the benzene ring in the formula (I) is 1-2, and the substituent R is hydrogen, C1-C4 alkyl, trifluoromethyl, C1-C4 alkoxy or halogen.

2. The benzoxazinone compound containing isoxazole heterocycle according to claim 1, wherein the substituent R on the benzene ring in formula (I) is 2, 4-dichloro, p-fluoro, p-methyl, m-methyl, p-trifluoromethyl, o-methoxy, p-bromo, o-bromo, 3, 5-dimethyl, p-ethoxy, hydrogen, p-isobutyl, p-isopropoxy, p-tert-butyl, p-isopropyl, p-chloro, p-ethyl, 2, 3-dimethyl, m-fluoro or m-phenoxy.

3. A process for the preparation of the isoxazole heterocycle-containing benzoxazinone compound according to claim 1, characterized by comprising the steps of;

1) 2, 4-difluoro nitrobenzene is taken as a raw material and reacts with sodium hydroxide in a water solvent to generate 5-fluoro-2-nitrophenol;

2) Using DMF as a solvent, using 5-fluoro-2-nitrophenol as a raw material, and reacting with ethyl bromoacetate in the presence of potassium carbonate to generate a compound shown as a formula (II);

3) Reacting a compound (II) serving as a raw material with reduced iron powder and glacial acetic acid to generate a compound shown as a formula (III);

4) Reacting a compound (III) serving as a raw material with concentrated nitric acid and concentrated sulfuric acid to generate a compound shown as a formula (IV);

5) Using DMF as a solvent, using a compound (IV) as a raw material, and reacting with bromopropyne in the presence of cesium carbonate to generate a compound shown as a formula (V);

6) Taking methanol-water mixed solution with the volume ratio of 1-4:1 as a solvent, taking a compound (VI) as a raw material, and reacting with hydroxylamine hydrochloride and potassium carbonate to generate a compound shown as a formula (VII);

7) Using dichloromethane as a solvent, using a compound (VII) as a raw material, reacting with NCS, and directly adding triethylamine and the compound (V) obtained in the step 5) after the reaction is finished to generate a benzoxazinone compound containing isoxazole heterocycle as shown in a formula (I);

the substituents R in the formulae (VI) and (VII) are the same as in the formula (I).

4. The method for preparing the isoxazole heterocycle-containing benzoxazinone compound according to claim 3, wherein the reaction temperature is 50-60 ℃ and the reaction time is 6-8h, and the molar ratio of 2, 4-difluoronitrobenzene to sodium hydroxide is 1:2-4 when 5-fluoro-2-nitrophenol is synthesized in the step 1).

5. The process for producing an isoxazole heterocycle-containing benzoxazinone compound according to claim 3, wherein the amount ratio of the substances of 5-fluoro-2-nitrophenol, potassium carbonate and ethyl bromoacetate is 1:1.2 to 1.3 when the compound represented by the formula (ii) is synthesized in step 2): 1.05-1.1.

6. The process for producing a benzoxazinone compound containing an isoxazole heterocycle according to claim 3, wherein the reaction time is 4 to 6 hours, the reaction temperature is 75 to 85 ℃ and the molar ratio of the compound (II) to the reduced iron powder is 1:1.5 to 2.5, and the concentration of the compound (II) in glacial acetic acid is 0.45 to 0.5mol/L when the compound represented by the formula (III) is synthesized in the step 3).

7. The method for producing a benzoxazinone compound containing an isoxazole heterocycle according to claim 3, wherein when the compound represented by the formula (iv) is synthesized in the step 4), the ratio of the amount of the compound represented by the formula (iii) to the amount of the substance of concentrated nitric acid is 1:1.5-4, wherein the mass fraction of the concentrated sulfuric acid is 75-85%, and the concentration of the compound shown in the formula (III) in the concentrated sulfuric acid is 0.1-0.15 mol/L.

8. The method for producing a benzoxazinone compound containing an isoxazole heterocycle according to claim 3, wherein when the compound represented by formula (v) is synthesized in step 5), the ratio of the amount of the compound represented by formula (iv) to the amount of the bromopropyne substance is 1:1.05-1.3, the ratio of the amount of the compound represented by the formula (IV) to the amount of the substance cesium carbonate being 1:1.2-1.3;

in the synthesis of the compound represented by the formula (VII) in the step 6), the amount ratio of the compound represented by the formula (VI), potassium carbonate and hydroxylamine hydrochloride is 1:1.2-1.3:1.2-1.3.

9. The method for producing a benzoxazinone compound containing an isoxazole heterocycle according to claim 3, wherein when the benzoxazinone compound containing an isoxazole heterocycle is synthesized in step 7), the ratio of the amounts of the compound represented by formula (vii), NCS, triethylamine and the compound represented by formula (v) is 1:1.2-1.3:1.2-1.4:1.1-1.2.

10. Use of the isoxazole heterocycle-containing benzoxazinone compound according to claim 1 or 2 in the preparation of herbicides.