Benzooxazinone Compounds Containing Thioquinazolinone Ring, Preparation Method Thereof and Application Thereof

Abstract

The present invention discloses benzoxazinone compounds containing a thioquinazolinone ring, a preparation method thereof, and applications thereof. The structural formula of the benzoxazinone compounds containing a thioquinazolinone ring is shown as formula (I): In formula (I), the substituent R is a C1-C4 alkyl group, hydrogen, ethynyl, vinyl, propynyl, 4-pentenyl, phenyl, or a substituted phenyl group, and the substituents of the substituted phenyl group are C1-C4 alkyl groups, nitro groups, halogen atoms, or cyano groups. The structure of the product obtained in the present invention was confirmed by 1H NMR, and herbicidal activity tests were conducted on 24 target products obtained. The results show that during the inhibition of the growth of wheat stems, at a high concentration of 100 ppm, the inhibition rates of compounds I-7, I-14, I-18, and I-19 all exceeded 90%. Among them, I-18 in this series of compounds had the best inhibitory effect on wheat stems, with an inhibition rate of 98.7%. When the concentration was 10 ppm, the inhibition rate could still reach 88.4%. Followed by I-7 with an inhibition rate of 80.6%.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis and pharmaceutical applications, and particularly relates to a benzoxazinone compound containing a thioquinazolinone ring, and a preparation method and application thereof. Background Art

[0002] With the development of society and the improvement of people's awareness of safety and environmental protection, the requirements for the use of pesticides are also increasing day by day. To solve this dilemma, pesticide chemists still need to make unremitting efforts to continue developing new pesticides with high efficiency and low toxicity. At present, developing safer pesticides with higher activity and lower toxicity has become a trend in the research direction of pesticide scientists. Protoporphyrinogen oxidase inhibitors have a wide range of biological activities, and the research on the related activities of new compounds thereof has certain theoretical significance, and it is expected to discover green and ideal pesticides. Because protoporphyrinogen oxidase inhibitors have many advantages, their research and development have received more and more extensive attention in recent years. Summary of the Invention

[0003] The purpose of the present invention is to provide a benzoxazinone compound containing a thioquinazolinone ring, and a preparation method and application thereof.

[0004] In order to study safer pesticides that are greener and less toxic, the present invention uses flumioxazin as a lead compound, retains the 1,4-benzoxazinone skeleton of flumioxazin, replaces the imide structure fragment of flumioxazin with a thioquinazolinone ring, and designs and synthesizes novel benzoxazinone compounds containing a thioquinazolinone ring by changing the groups connected to the uracil ring and the nitrogen atom.

[0005] The benzoxazinone compound containing a thioquinazolinone ring has a structural formula as shown in formula (I):

[0006]

[0007] In formula (I), the substituent R is a C1-C4 alkyl group, hydrogen, ethynyl, vinyl, propynyl, 4-pentenyl, phenyl or substituted phenyl, and the substituent of the substituted phenyl is a C1-C4 alkyl group, nitro, halogen or cyano.

[0008] Preferably, the substituent of the substituted phenyl is p-nitro, p-tert-butyl, o-bromo, m-bromo, p-bromo, p-fluoro, p-chloro, p-n-butyl, o-methyl, m-methyl, p-methyl or p-cyano.

[0009] The preparation method of the benzoxazinone compound containing a thioquinazolinone ring includes the following steps;

[0010] 1) Using 2,4-difluoronitrobenzene as a raw material, reacting with sodium hydroxide in an aqueous solvent to generate 5-fluoro-2-nitrophenol;

[0011] 2) Using DMF as the solvent, reacting 5-fluoro-2-nitrophenol as the raw material with ethyl bromoacetate in the presence of potassium carbonate to form the compound shown in formula (Ⅱ);

[0012] 3) Using the compound (Ⅱ) as the raw material, reacting with reduced iron powder and glacial acetic acid to form the compound shown in formula (Ⅲ);

[0013] 4) Using the compound (Ⅲ) as the raw material, reacting with concentrated nitric acid and concentrated sulfuric acid to form the compound shown in formula (Ⅳ);

[0014] 5) Using DMF as the solvent, reacting the compound (Ⅳ) as the raw material with propargyl bromide in the presence of cesium carbonate to form the compound shown in formula (Ⅴ);

[0015] 6) Using ethanol as the solvent, reacting the compound (Ⅴ) and saturated ammonium chloride aqueous solution as the raw materials in the presence of iron powder to form the compound shown in formula (Ⅵ);

[0016] 7) Using the compound (Ⅶ) as the raw material, reacting with methanol in the presence of concentrated sulfuric acid to form the compound shown in formula (Ⅷ);

[0017] 8) Using ethanol as the solvent, reacting the compound (Ⅷ) as the raw material with carbon disulfide and triethylamine, and then reacting with di-tert-butyl dicarbonate to form the compound shown in formula (Ⅸ);

[0018] 9) Using 1,4-dioxane as the solvent, reacting the compound (Ⅸ) as the raw material with the compound (Ⅵ) prepared in step 6) in the presence of triethylamine to form the compound shown in formula (Ⅹ);

[0019] 10) Using DMF as the solvent, reacting the compound (Ⅹ) as the raw material with the compound (Ⅺ) in the presence of cesium carbonate to form the benzoxazinone compound containing a thioquinazolinone ring shown in formula (Ⅰ);

[0020]

[0021]

[0022] The substituent R in formula (Ⅺ) is the same as that in formula (Ⅰ). The substituent X in formula (Ⅺ) is a halogen.

[0023] The reaction process is as follows:

[0024]

[0025] 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.

[0026] Further, when synthesizing the compound shown in formula (II) in step 2), the molar ratio of 5-fluoro-2-nitrophenol, potassium carbonate and ethyl bromoacetate is 1:1.2 - 1.3:1.05 - 1.1.

[0027] Further, when synthesizing the compound shown in formula (III) in step 3), the reaction time is 4 - 6 h, the reaction temperature is 75 - 85 °C, the molar ratio of the compound (II) to 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.

[0028] Further, when synthesizing the compound shown in formula (IV) in step 4), the molar ratio of the compound shown in 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 shown in formula (III) in concentrated sulfuric acid is 0.1 - 0.15 mol / L.

[0029] Further, when synthesizing the compound shown in formula (V) in step 5), the molar ratio of the compound shown in formula (IV) to propargyl bromide is 1:1.05 - 1.3, and the molar ratio of the compound shown in formula (IV) to cesium carbonate is 1:1.2 - 1.3.

[0030] Further, when synthesizing the compound shown in formula (VI) in step 6), the molar ratio of the compound shown in formula (V) to iron powder is 1:2 - 3, and the volume ratio of the amount of the compound shown in formula (V) to the volume of saturated ammonium chloride aqueous solution is 1 mmol:

[0031] (1.2 - 2.0) mL.

[0032] Further, when synthesizing the compound shown in formula (VIII) in step 7), the mass fraction of the concentrated sulfuric acid is 75 - 85%, the volume ratio of the concentrated sulfuric acid to methanol is 1:4 - 6, and the volume ratio of the amount of the compound (VII) to the volume of methanol is 1 mmol:(1 - 1.5) mL.

[0033] Further, when synthesizing the compound shown in formula (IX) in step 8), the molar ratio of the compound shown in formula (VIII), carbon disulfide and di-tert-butyl dicarbonate is 1:9 - 11:1 - 1.1.

[0034] Further, when synthesizing the compound shown in formula (X) in step 9), the molar ratio of the compound shown in formula (VI), the compound shown in formula (IX) and triethylamine is 1:1.05 - 1.25:3.

[0035] Further, in step 10), when synthesizing the benzoxazinone compound containing a thioquinazolinone ring, the molar ratio of the compound shown in formula (Ⅹ), the compound shown in formula (Ⅺ), and cesium carbonate is 1:2:1.2 - 1.5.

[0036] Use of the above-mentioned benzoxazinone compound containing a thioquinazolinone ring in the preparation of herbicides.

[0037] The beneficial effects of the present invention are as follows:

[0038] The structure of the product obtained in the present invention was confirmed by 1H NMR, and the herbicidal activities of the 24 target products obtained were tested. The results showed that: at a high concentration of 100 ppm, the inhibitory effect of all compounds on the radicles of rape was not obvious as a whole. During the inhibition of the growth of wheat stems, at a high concentration of 100 ppm, the inhibition rates of compounds I-7, I-14, I-18, and I-19 all exceeded 90%. Among them, the inhibitory effect of I-18 on wheat stems in this series of compounds was the best, with an inhibition rate of 98.7%. When the concentration was 10 ppm, the inhibition rate could still reach 88.4%. Followed by I-7 with an inhibition rate of 80.6%. Specific Embodiments

[0039] 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.

[0040] Example 1

[0041] 1) Preparation of 5-fluoro-2-nitrophenol

[0042] Add 2,4-difluoronitrobenzene (100.00 mmol) and 10 mL of water into a 100 mL round-bottom reaction flask. After heating to raise the temperature of the reaction system to 55 °C, slowly add 40.00 g of 30% sodium hydroxide aqueous solution dropwise with stirring. After about 15 min of dropping, continue to stir at 55 °C for 6 h. After the reaction is completed, cool the reaction solution to room temperature, then add dilute hydrochloric acid dropwise to adjust the pH = 2, and finally extract it three times with 60 mL of dichloromethane. Combine the organic phases, and remove the dichloromethane solvent by rotary evaporation under reduced pressure to obtain 10.70 g of the crude product of 5-fluoro-2-nitrophenol. Without purification, it is directly used in the next step of the reaction. Yield: 68%, yellow solid, melting point: 32 - 33 °C.

[0043] 2) Preparation of the compound shown in formula (Ⅱ)

[0044] Weigh 5-fluoro-2-nitrophenol (51.08 mmol) and potassium carbonate (63.87 mmol) and add them to a 100 mL round-bottom reaction flask. Then add 60 mL of DMF solution to dissolve them. Stir for about 15 min at room temperature, and then slowly add ethyl bromoacetate (53.66 mmol). Track the reaction by TLC (V EA / V PE = 1:6). After the reaction is completed in about 12 h, pour the reaction solution into a beaker, then add 50 mL of water and 50 mL of ethyl acetate for extraction. After extraction, wash the organic layer with saturated sodium chloride solution two to three times, dry the organic phase with anhydrous sodium sulfate, and finally remove the ethyl acetate solvent by rotary evaporation under reduced pressure and recrystallize with ethanol to obtain 8.84 g of the compound shown in formula (Ⅱ), an oily liquid, yield: 71.1%.

[0045] 3) Preparation of the compound shown in formula (Ⅲ)

[0046] Add the compound shown in formula (Ⅱ) (29.05 mmol) and 60 mL of glacial acetic acid to a 250 mL three-necked round-bottom reaction flask and stir. Heat to raise the temperature of the reaction system to 80 °C and then maintain a reflux state. Subsequently, weigh reduced iron powder (58.10 mmol) and add it to the reaction system in three batches within 20 min. Track the reaction by TLC (V EA / V PE = 1:4). After the reaction is completed in about 4 h, cool the reaction solution to room temperature and then pour it into 100 mL of ice water until a large amount of white precipitate precipitates out in the reaction solution. After the white precipitate is filtered by suction, washed with water and dried, finally 3.20 g of the compound shown in formula (Ⅲ) is obtained, yield: 65.9%, a white solid, melting point: 203 - 204 °C.

[0047] 4) Preparation of the compound shown in formula (Ⅳ)

[0048] Slowly add the compound shown in formula (Ⅲ) (10.65 mmol) and 80 mL of freshly prepared sulfuric acid solution with a mass fraction of 80% to a 250 mL three-necked round-bottom reaction flask and stir. Add an appropriate amount of ice cubes to cool the system to 0 °C, and then drop 1.78 g of nitric acid with a mass fraction of 65% and 5 mL of sulfuric acid with a mass fraction of 80% into it within 10 min. Track the reaction by TLC (V EA / V PEThe reaction was monitored by TLC (V / V = 1:3). After about 45 min, when the reaction was completed, the reaction solution was poured into 100 mL of ice water and stirred well for 30 min. A large amount of yellow precipitate separated out from the system. The yellow precipitate was collected by suction filtration, washed with water, and finally dried to obtain 2.02 g of the compound shown in formula (IV), with a yield of 89.4%, a pale yellow solid, and a melting point of 207 - 208 °C.

[0049] 5) Preparation of the compound shown in formula (V)

[0050] The compound shown in formula (IV) (7.14 mmol) and cesium carbonate anhydrous (8.93 mmol) were added to a 100 mL round-bottom reaction flask, 50 mL of DMF solution was added, and the mixture was stirred at room temperature for about 15 min. Then, propargyl bromide (7.50 mmol) was slowly added dropwise over about 10 min. After the addition was complete, the mixture was stirred overnight. After the reaction was completed, the reaction solution was poured into a separatory funnel, then 50 mL of water and 50 mL of ethyl acetate were added for extraction. The organic layer was washed three times with saturated sodium chloride solution and dried over an appropriate amount of anhydrous sodium sulfate. Finally, the ethyl acetate was removed under reduced pressure and the residue was subjected to column chromatography. The compound shown in formula (V) was separated and purified using an eluent with V EA / V PE / V = 1:4 to obtain 1.51 g of the compound shown in formula (V), with a yield of 84.5%, a yellow solid, and a melting point of 108 - 109 °C.

[0051] 6) Preparation of the compound shown in formula (VI)

[0052] The compound shown in formula (V) (6.00 mmol) and 20 mL of 95% ethanol were added to a 100 mL reaction flask. Subsequently, 10 mL of saturated ammonium chloride aqueous solution was added, and the mixture was stirred well and heated to reflux. Then, reduced iron powder (12 mmol) was weighed and added to the reaction system in three portions within 20 min. The reaction was monitored by TLC. After about 3 h, when the reaction was completed, the hot reaction mixture was first filtered by suction and washed with 50 mL of ethyl acetate. Subsequently, the filtrate was poured into a separatory funnel and washed with 20 mL of water and 20 mL of brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and then subjected to column chromatography. The compound (VI) was separated using an eluent with V EA / V PE / V = 1:5 to obtain 1.05 g of the compound, with a yield of 79.2%, a pale yellow solid, and a melting point of 180 - 181 °C.

[0053] 7) Preparation of the compound shown in formula (VIII)

[0054] In a 250 mL three-necked flask, add 50 mL of methanol. Slowly dropwise add 10 mL of concentrated sulfuric acid with a mass fraction of 80% under an ice bath condition. After the addition is complete, restore to room temperature and stir. Subsequently, add compound (Ⅶ) (40.00 mmol), heat up to reflux. After reacting for 2 - 3 h until the raw materials are completely reacted, pour the reaction solution into 300 mL of ice water, adjust the pH = 7 with sodium bicarbonate (or ammonia water), and cool for crystallization; filter, wash with water, and dry to obtain 2.89 g of brown crude product with a yield of 47.9%. Decolorize the crude product with methanol, then a large amount of bright yellow crystals precipitate. After filtration, wash with methanol and dry to obtain 5.98 g of yellow crystals, yield: 79.2%.

[0055] 8) Preparation of the compound shown in formula (Ⅸ)

[0056] Add compound (Ⅷ) (16.62 mmol) and 20 mL of absolute ethanol to a 100 mL three-necked flask. While stirring, slowly add CS2 (166.20 mmol) and triethylamine (16.62 mmol) dropwise within 10 min. Subsequently, stir the reaction solution at room temperature for about 40 min, then cool under an ice bath condition. Take a catalytic amount of DMAP (36.65 mg, 0.3 mmol) and di-tert-butyl dicarbonate (16.47 mmol), dissolve them in 5 mL of absolute ethanol and dropwise add to the above reaction solution. Finally, raise the temperature to room temperature, and the reaction ends after about 1 h. Filter the mixture to remove triethylamine hydrochloride, and rotary evaporate the solvent under reduced pressure to obtain 1.77 g of crude product of compound (Ⅸ), an oily droplet, yield: 55.2%, which is directly used for the next step of reaction without purification.

[0057] 9) Preparation of the compound shown in formula (Ⅹ)

[0058] Add compound (Ⅵ) (1.00 mmol) and 20 mL of 1,4-dioxane to a 100 mL reaction flask. Subsequently, add triethylamine (3.00 mmol) and stir at room temperature for about 30 min. Then, dissolve the compound (Ⅸ) prepared in the previous step (1.10 mmol) in 5 mL of 1,4-dioxane, and slowly dropwise add it to the above amine solution while stirring. After the addition is complete, heat to reflux. TLC (V EA / V PE = 1:6) is used to monitor the reaction. After the reaction ends in about 12 h, pour the reaction solution into a separatory funnel, then add 50 mL of water and 50 mL of ethyl acetate for extraction. Wash the organic phase with saturated sodium carbonate solution and dry with anhydrous sodium sulfate. Finally, rotary evaporate the ethyl acetate solvent under reduced pressure and column chromatograph, and separate and purify with an eluent of V EA / V PE = 1:6 to obtain 292.52 mg of compound (Ⅹ) with a yield of 76.6% and a melting point: 140 - 141 °C.

[0059] 10) Preparation of Compounds I-1 to I-24

[0060] Compound (X) (0.25 mmol) and cesium carbonate (0.31 mmol) were added to a 100 mL reaction flask, and then 30 mL of DMF was added to dissolve it. After stirring for 20 min, compound (XI) (0.50 mmol) was added. After reacting for 12 h at room temperature, 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 with saturated sodium chloride two to three times and then dried with anhydrous sodium sulfate. Finally, the ethyl acetate solvent was rotary evaporated under reduced pressure and loaded onto a column, and the target compound was separated and purified with an eluent of V EA / V PE = 1:5 to obtain the target compound finally.

[0061] The above process was repeated for the preparation method of the target compounds I-1 to I-24. The structural formula of compound (XI) was RCH2Cl, and the substituent R in compound (XI) was the same as the substituents of the target compounds I-1 to I-24, which were listed in Table 1. The yields and physicochemical data of the finally obtained target products were summarized in Table 1. The 1H NMR characterization data of the target compounds I-1 to I-24 were summarized in Table 2.

[0062] Table 1 Physicochemical Data of Benzooxazinone Compounds Containing Thioquinazolinone Ring

[0063]

[0064]

[0065] Table 2 1H NMR Data of Benzooxazinone Compounds Containing Thioquinazolinone Ring

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072] Example 2 Herbicidal Activity Test

[0073] Test Method

[0074] (1) Test subjects: Seeds of the dicotyledonous plant Brassica napus and the monocotyledonous plant Triticum aestivum.

[0075] (2) Test treatments: Before the bioactivity test, the seeds were sterilized. First, the seeds were soaked in a 5%-10% sodium hypochlorite solution for about 10 minutes for sterilization. After soaking for 5 hours, they were repeatedly rinsed with deionized water from a Millipore ultrapure water system and then air-dried in a sterile environment.

[0076] (3) Test methods: Weigh 2 mg of the test compound into a 5 mL EP tube, pipette 2 mL of acetone into it and shake well to completely dissolve the test compound to prepare a 1 mg / L stock solution for standby. Take 1 mL of the stock solution into a 10 mL EP tube and add 9 mL of deionized water to dilute it to obtain a 100 ppm test solution. Take 1 mL of the solution from the previous step into a 10 mL EP tube and add 9 mL of deionized water to dilute it to obtain a 10 ppm test solution. Another compound, flumioxazin, was used as a control drug.

[0077] Wheat bioactivity test: Acetone was used as the solvent in the experiment. All bioassays were performed in duplicate and in cups. During the experiment, contamination caused by the external environment should be avoided. A filter paper with a diameter of 7.5 cm was laid flat in it, 10 mL of the test compound solution with a certain concentration was added, and 10 wheat seeds were sown and cultured in the natural environment. After about one week, the height of the wheat seedlings was measured, and the herbicidal activity of the target compound was detected by the growth inhibition of the plant height of the wheat seedlings. Activity index: Plant height growth inhibition rate (%).

[0078] Rapeseed bioactivity test: Acetone was used as the solvent in the experiment. All bioassays were performed in duplicate and in a sterile and pyrogen-free polystyrene 24-well cell culture plate (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, the sample wells were covered and sealed with raw tape; incubation was carried out under dark conditions at room temperature. After about one week, the radicle length was measured. Activity index: Radicle growth inhibition rate (%).

[0079] Inhibition rate calculation:

[0080]

[0081] The results of the activity test are shown in Table 3:

[0082] Herbicidal Activity of Benzoxazinone Compounds Containing Thioquinazolinone Ring

[0083]

[0084] The herbicidal activity results of benzoxazinone compounds containing thioquinazolinone ring (24 compounds) show that (Table 3), at a high concentration of 100 ppm, I-1 to I-24 have no inhibitory effect on the radicles of rape. Only I-12 and I-18 have an inhibition rate on the stems of wheat exceeding 60%. Generally, the inhibitory effect on the radicles of rape is very insignificant and the activity is poor. During the inhibition of the growth of wheat stems, at a high concentration of 100 ppm, the inhibition rates of compounds I-7, I-14, I-18, and I-19 all exceed 90%. Among them, I-18 in this series of compounds has the best inhibitory effect on the stems of wheat, with an inhibition rate of 98.7%. When the concentration is 10 ppm, the inhibition rate can still reach 88.4%. Followed by I-7 with an inhibition rate of 80.6%.

[0085] The content described in this specification is only a list 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 stated in the embodiments. The protection scope of the present invention is also only equivalent technical means that can be conceived by those skilled in the art based on the inventive concept of the present invention.

Claims

1. Use of benzoxazinone compounds containing a thioquinazolinone ring in the preparation of herbicides, characterized in that The herbicide is used to inhibit monocotyledonous plant wheat; The structural formula of the benzoxazinone compound containing a thioquinazolinone ring is shown in Formula (Ⅰ): In Formula (I), the substituent R is p-NO2-Ph, p-F-Ph, p-CN-Ph or n-butyl.

2. The application according to claim 1, characterized in that A preparation method of the benzoxazinone compound containing a thioquinazolinone ring comprises the following steps; 1) Using 2,4-difluoronitrobenzene as a raw material, reacting with sodium hydroxide in an aqueous solvent to generate 5-fluoro-2-nitrophenol; 2) Using DMF as a solvent, using 5-fluoro-2-nitrophenol as a raw material, reacting with ethyl bromoacetate in the presence of potassium carbonate to generate a compound shown in Formula (Ⅱ); 3) Using the compound (Ⅱ) as a raw material, reacting with reduced iron powder and glacial acetic acid to generate a compound shown in Formula (Ⅲ); 4) Using the compound (Ⅲ) as a raw material, reacting with concentrated nitric acid and concentrated sulfuric acid to generate a compound shown in Formula (Ⅳ); 5) Using DMF as a solvent, using the compound (Ⅳ) as a raw material, reacting with propargyl bromide in the presence of cesium carbonate to generate a compound shown in Formula (Ⅴ); 6) Using ethanol as a solvent, using the compound (Ⅴ) and saturated ammonium chloride aqueous solution as raw materials, reacting in the presence of iron powder to generate a compound shown in Formula (Ⅵ); 7) Using the compound (Ⅶ) as a raw material, reacting with methanol in the presence of concentrated sulfuric acid to generate a compound shown in Formula (Ⅷ); 8) Using ethanol as a solvent, using the compound (Ⅷ) as a raw material, reacting with carbon disulfide and triethylamine, and then reacting with di-tert-butyl dicarbonate to generate a compound shown in Formula (Ⅸ); 9) Using 1,4-dioxane as a solvent, using the compound (Ⅸ) as a raw material, reacting with the compound (Ⅵ) prepared in step 6) in the presence of triethylamine to generate a compound shown in Formula (Ⅹ); 10) Using DMF as a solvent, using the compound (Ⅹ) as a raw material, reacting with the compound (Ⅺ) in the presence of cesium carbonate to generate the benzoxazinone compound containing a thioquinazolinone ring shown in Formula (Ⅰ); The substituent R in Formula (Ⅺ) is the same as that in Formula (Ⅰ), and the substituent X in Formula (Ⅺ) is a halogen.

3. The application according to claim 2, wherein 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; When synthesizing the compound shown in Formula (Ⅱ) in step 2), the molar ratio of 5-fluoro-2-nitrophenol, potassium carbonate and ethyl bromoacetate is 1:1.2-1.3:1.05-1.

1.

4. The application according to claim 2, wherein When synthesizing the compound shown in Formula (Ⅲ) in step 3), the reaction time is 4-6 h, the reaction temperature is 75-85 °C, the molar ratio of the compound (Ⅱ) to 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; When synthesizing the compound shown in Formula (Ⅳ) in step 4), the molar ratio of the compound shown in 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 shown in Formula (Ⅲ) in concentrated sulfuric acid is 0.1-0.15 mol / L.

5. The application according to claim 2, characterized in that When synthesizing the compound shown in formula (V) in step 5), the molar ratio of the compound shown in formula (IV) to propargyl bromide is 1:1.05 - 1.3, and the molar ratio of the compound shown in formula (IV) to cesium carbonate is 1:1.2 - 1.3; When synthesizing the compound shown in formula (VI) in step 6), the molar ratio of the compound shown in formula (V) to iron powder is 1:2 - 3, and the molar ratio of the amount of substance of the compound shown in formula (V) to the volume of saturated ammonium chloride aqueous solution is 1 mmol:(1.2 - 2.0) mL.

6. The application according to claim 2, wherein When synthesizing the compound shown in formula (VIII) in step 7), the mass fraction of concentrated sulfuric acid is 75 - 85%, the volume ratio of concentrated sulfuric acid to methanol is 1:4 - 6, and the molar ratio of the amount of substance of compound (VII) to the volume of methanol is 1 mmol:(1 - 1.5) mL; When synthesizing the compound shown in formula (IX) in step 8), the molar ratio of the compound shown in formula (VIII), carbon disulfide, and di-tert-butyl dicarbonate is 1:9 - 11:1 - 1.

1.

7. The application according to claim 2, characterized in that When synthesizing the compound shown in formula (X) in step 9), the molar ratio of the compound shown in formula (VI), the compound shown in formula (IX), and triethylamine is 1:1.05 - 1.25:

3.

8. The application according to claim 2, characterized in that When synthesizing the benzoxazinone compound containing a thioquinazolinone ring shown in formula (I) in step 10), the molar ratio of the compound shown in formula (X), the compound shown in formula (XI), and cesium carbonate is 1:2:1.2 - 1.5.

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