N-phenyl triazinone derivative as well as preparation method and application thereof

Abstract

The invention relates to the technical field of compound synthesis and pesticides, in particular to an N-phenyl triazinone derivative and a preparation method and application thereof.The N-phenyl triazinone derivative has the 100% control effect on broadleaf weeds under the dosage of 37.5 a.i g / ha-150 a.i g / ha, and part of compounds have the good control effect on grassy weeds; the compound can obtain a better weeding effect at a low dosage, can be used as a potential PPO inhibitor and broadleaf weed post-emergence herbicide for development and use, and has the advantages of novel structure, simple preparation process, low production cost and wide application prospect.

Description

Technical Field

[0001] The invention belongs to the field of compound pesticides, and specifically relates to an N-phenyl triazone derivative and a preparation method and application thereof. Background Art

[0002] Herbicides play a vital role in modern agriculture, effectively controlling weeds and increasing crop yields. Over the past few decades, the development and application of herbicides have undergone tremendous changes due to the need to address emerging challenges such as weed resistance, environmental issues, and the need for sustainable agriculture. Therefore, the development of efficient and green herbicides is a major demand in current agricultural production.

[0003] Protoporphyrinogen oxidase (PPO) catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX and is one of the most important targets for herbicide discovery. Protoporphyrinogen oxidase is the penultimate enzyme in the biosynthesis of chlorophyll and heme. It belongs to the large family of enzymes containing flavonoid adenine dinucleotide (FAD). It catalyzes the conversion of protoporphyrinogen IX to protoporphyrin IX. The inhibition of PPO by plants can lead to the toxic accumulation of protoporphyrin IX in the cytoplasm. Under light, protoporphyrin IX reacts with oxygen to produce a lot of reactive oxygen species, destroying the cell membrane and causing rapid burn symptoms in plants. On the other hand, PPO inhibitors have many advantages such as a wide spectrum of herbicides, strong drug resistance, environmental friendliness, low toxicity and low usage rate. N-phenylthiotriazineone is a PPO inhibitor structure with a relatively new skeleton and a new mechanism of action. The design and synthesis of herbicide small molecules based on N-phenyltriazineone units is very consistent with the current trend of new pesticide creation.

[0004] Application No. 201911038131.8 discloses a "triazine ketone compound and its use".

[0005]

[0006] Application No. 201910419966.1 discloses a "thiotriazine ketone isoxazoline compound and its preparation method and application, protoporphyrinogen oxidase inhibitor and herbicide"

[0007]

[0008] These compounds have a wide herbicidal spectrum and are highly effective and have long-lasting herbicidal activity, especially against broadleaf weeds. However, at the same time, these compounds cause serious damage to broadleaf crops and their safety still needs to be improved.

[0009] In addition, most existing herbicides (including the herbicide with the above structure disclosed in CN105753853A) not only have a wide spectrum of weed control, but also cause very serious damage to dicotyledonous crops, which makes it difficult to apply these herbicides to dicotyledonous crop fields. Therefore, it is very necessary to develop a herbicide that is safe for crops.

[0010] In addition, the patents with publication numbers CN117603147A and CN117486818A are the preliminary research results of the present invention team. In the patent technology of CN117603147A, although the A5 compound showed excellent herbicidal activity against barnyard grass, crabgrass, foxtail grass, velvetleaf, Amaranthus retroflexus, and Purslane at a dosage of 37.5 g a.i. / ha, its yield was low, only 66.83%, and the effect on crops was Safety is unknown; target compounds such as A34 and A43 in the patent technology of CN117486818A show excellent herbicidal activity against barnyard grass, crabgrass, foxtail grass, velvetleaf, Amaranthus retroflexus, and purslane at 37.5 ga.i. / ha, and show crop safety superior to trifluoperazine for crops such as rice, corn, wheat, peanuts, soybeans, and cotton, but their yields are low, at 60.01% and 57.89%, respectively. Therefore, it is of great practical significance to find a herbicide with stable and high yield. Summary of the invention

[0011] In view of the deficiencies of the prior art, the present invention provides an N-phenyl triazone derivative and a preparation method and application thereof.

[0012] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0013] One of the purposes of the present invention is to provide: an N-phenyl triazone derivative, the structural formula of the N-phenyl triazone derivative is as follows:

[0014]

[0015] In formula (I):

[0016] X 1 , X 2 , X 3 Respectively selected from O, S, NCH3, N(CH3)2, NCN or NOCH3;

[0017] X 4 Selected from O, S, NR 11 ONCR 8 ,

[0018] R 1 , R 2 are respectively selected from C1-C6 alkyl or C1-C6 haloalkyl;

[0019] R 3 , R 4 are respectively selected from H, halogen, -CN, C1-C6 alkyl, (C1-C6 haloalkyl)-O- or (C1-C6 alkyl)-SO2-;

[0020] R 5 are respectively selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy;

[0021] R 6 are respectively selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy;

[0022] R 7 are respectively selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy;

[0023] R 8 are respectively selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy;

[0024] R 9 are respectively selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 cyano;

[0025] R 10 are selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 cyano, (CH2)nCOX 5 R 11 ;

[0026] n is selected from 0, 1, 2, 3, 4, 5, 6

[0027] X 4 Selected from O, S, NR 12 ONCR 13 ,

[0028] R 11are respectively selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C4 alkoxy C1-C6-alkyl, C1-C4 haloalkoxy C1-C6 alkyl;

[0029] R 12 are respectively selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C4 alkoxy C1-C6-alkyl, C1-C4 haloalkoxy C1-C6 alkyl;

[0030] R 13 are respectively selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C4 alkoxy C1-C6-alkyl, C1-C4 haloalkoxy C1-C6 alkyl;

[0031] The N-phenyl triazone derivatives include the following compounds:

[0032] Compound E1: (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate;

[0033] Compound E2: (E)-ethyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate;

[0034] Compound E3: (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate;

[0035] Compound E4: (E)-butyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate;

[0036] Compound E5: (E)-pentyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate;

[0037] Compound E6: (E)-benzyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate;

[0038] Compound E7: (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate;

[0039] Compound E8: (E)-ethyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate;

[0040] Compound E9: (E)-propyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate;

[0041] Compound E10: (E)-butyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate;

[0042] Compound E11: (E)-pentyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate;

[0043] Compound E12: (E)-tert-butyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate;

[0044] Compound E13: 2-methoxy-2-oxoethyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate;

[0045] Compound E14: 1-ethoxy-1-oxopropan-2-yl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate;

[0046] Compound E15: 3-methoxy-3-oxopropyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate;

[0047] Compound E16: ((E)-2-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)acetate;

[0048] Compound E17: (E)-2-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)propanoate;

[0049] Compound E18: (E)-3-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)propanoate;

[0050] Compound E19: (E)-methyl 3-(2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionamido)propanoate;

[0051] Compound E20: (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-2-methylpropanoate;

[0052] Compound E21: (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-2-methylpropanoate;

[0053] Compound E22: (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butanoate;

[0054] Compound E23: (E)-ethyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butanoate

[0055] Compound E24: (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoate;

[0056] Compound E25: (E)-ethyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoate;

[0057] Compound E26: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester;

[0058] Compound E27: ethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-5,6-dihydro-4H-1,2-oxazine-6-carboxylate;

[0059] Compound E28: methyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-fluoro-5,6-dihydro-4H-1,2-oxazine-6-carboxylate;

[0060] Compound E29: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester;

[0061] Compound E30: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid ethyl ester;

[0062] Compound E31: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid propyl ester;

[0063] Compound E32: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid butyl ester;

[0064] Compound E33: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid isopropyl ester;

[0065] Compound E34: tert-butyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate;

[0066] Compound E35: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid isobutyl ester;

[0067] Compound E36: ​​2,2,2-trifluoroethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate;

[0068] Compound E37: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid cyclohexyl ester;

[0069] Compound E38: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid benzyl ester;

[0070] Compound E39: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid oxirane-2-ylmethyl ester;

[0071] Compound E40: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid (tetrahydrofuran-2-yl)methyl ester;

[0072] The second object of the present invention is to provide: a method for preparing the above-mentioned N-phenyl triazone derivative, comprising the following steps:

[0073] (1) Preparation of intermediate 2:

[0074] Take intermediate 1, ammonium chloride and 90% ethanol solution, mix and stir, heat to 80°C, then slowly add iron powder, make the reaction system react at 80°C for 4 hours, remove the remaining iron powder by suction filtration, and then extract, dry and column chromatography to obtain intermediate 2; intermediate 1 is substituted m-nitroacetophenone;

[0075] (2) Preparation of intermediate 3:

[0076] Triphosgene and toluene were added to a round-bottom flask and cooled to 0°C; intermediate 2 and triethylamine were added dropwise to the flask within 10 minutes, and the mixture was slowly heated to reflux; after 10 hours, the mixture was cooled to room temperature and the solvent was removed to obtain intermediate 3;

[0077] (3) Preparation of intermediate 4:

[0078] Toluene and N,N-dimethylthiourea are added to the intermediate 3, and then the solution is stirred at room temperature for 30 minutes; finally, CDI is added to the solution, and the solution is slowly heated to 85°C for 12 hours; after the reaction is completed, the reaction solution is cooled to room temperature, and then concentrated under reduced pressure, extracted, separated from the organic layer, washed, dried, concentrated, and column chromatographed to obtain the intermediate 4;

[0079] (4) Preparation of intermediate 5:

[0080] The intermediate 4 was dissolved in 80% ethanol, hydroxylamine hydrochloride was added, and the temperature was raised to 80°C for reaction for 4 hours; after the reaction was completed, the reaction solution was cooled to room temperature, and the intermediate 5 was obtained by extraction, separation of organic layer, washing, drying, concentration, and column chromatography;

[0081] (5) Preparation of intermediate 7:

[0082] The intermediate 4 was dissolved in 30% HBr (in acetic acid), and then Br2 was added dropwise in an ice bath, and stirred for 1 h in an ice bath. After the reaction was completed, it was poured into ice water, and then extracted, dried, and column chromatographed to obtain the intermediate 7;

[0083] (6) Preparation of intermediate 8:

[0084] The intermediate 7 was dissolved in 80% ethanol, hydroxylamine hydrochloride was added, and the temperature was raised to 80°C for reaction for 4 hours; after the reaction was completed, the reaction solution was cooled to room temperature, and the intermediate 8 was obtained by extraction, separation of organic layer, washing, drying, concentration, and column chromatography;

[0085] (7) Preparation of target compounds E1–E25:

[0086] The intermediate 5 is dissolved in DMF, potassium carbonate and a substituted 2-chlorocarboxylic acid derivative intermediate 6 are added, and the mixture is stirred at room temperature. After the reaction is completed, the mixture is sequentially subjected to extraction, separation of the organic layer, drying, and column chromatography to obtain N-phenyl triazone derivatives E1-E25; the intermediate 6 is a substituted 2-chlorocarboxylic acid derivative;

[0087] (8) Preparation of target compounds E26–E40:

[0088] The intermediate 8 was dissolved in ethyl acetate, and sodium carbonate and a substituted enoic acid derivative were added. The mixture was stirred at room temperature. After the reaction was completed, the N-phenyl triazone derivatives E26–E40 were obtained after extraction, separation of the organic layer, drying, and column chromatography.

[0089] In step (1), the molar ratio of the intermediate 1, ammonium chloride and iron powder is: intermediate 1: ammonium chloride: iron powder = 1:3:3; the amount of 90% ethanol is controlled by adding 1 mL of 90% ethanol per millimole of intermediate 1.

[0090] In step (2), the molar ratio of the intermediate 2, triphosgene and triethylamine is: intermediate 2: triphosgene: triethylamine = 1:1:0.2; the amount of toluene is controlled by adding 1 mL of toluene per millimole of intermediate 2.

[0091] In step (3), the molar ratio of the intermediate 3, N,N-dimethylthiourea and CDI is: intermediate 3: N,N-dimethylthiourea: CDI = 1:2:2; the amount of toluene is controlled by adding 1 mL of toluene per millimole of intermediate 3.

[0092] In step (4), the molar ratio of the intermediate 4 and hydroxylamine hydrochloride is: intermediate 4:hydroxylamine hydrochloride = 1:2; the amount of the 80% ethanol is controlled by adding 1 mL of 80% ethanol per millimole of the intermediate 4.

[0093] In step (5), the molar ratio of the intermediate 4 and Br2 is: intermediate 4:Br2=1:1.1; the 30% HBr (in acetic acid) is controlled by adding 1 mL of 30% HBr (in acetic acid) per mmol of the intermediate 4.

[0094] In step (6), the molar ratio of the intermediate 6 and hydroxylamine hydrochloride is: intermediate 6:hydroxylamine hydrochloride; and the 80% ethanol is controlled by adding 1 mL of 80% ethanol per mmol of the intermediate 6.

[0095] In step (7), the molar ratio of the intermediate 5, intermediate 6 and potassium carbonate is: intermediate 5: intermediate 6: potassium carbonate = 1: 1.25: 1.5; the amount of DMF is controlled by adding 1 mL of DMF per millimole of intermediate 5.

[0096] In step (8), the molar ratio of the intermediate 7, substituted enoic acid derivative and sodium carbonate is: intermediate 7: substituted enoic acid derivative: sodium carbonate = 1:1.25:1.5; the amount of ethyl acetate is controlled by adding 1 mL of ethyl acetate per millimole of intermediate 7.

[0097] The preparation route of the N-phenyl triazone derivative is any one of the following:

[0098] Route 1:

[0099]

[0100] Route 2:

[0101]

[0102] More preferably, the substituted m-nitroacetophenone is 1-(2-chloro-4-fluoro-5-nitrophenyl)ethan-1-one.

[0103] Further preferably, the substituted 2-chlorocarboxylic acid derivative is methyl 2-chloroacetate, ethyl chloroacetate, propyl chloroacetate, butyl chloroacetate, pentyl chloroacetate, benzyl chloroacetate, methyl 2-chloropropionate, ethyl 2-chloropropionate, propyl 2-chloropropionate, butyl 2-chloropropionate, pentyl 2-chloropropionate, tert-butyl 2-chloropropionate, 2-methoxy-2-oxoethyl 2-chloropropionate, 1-methoxy-1-oxopropan-2-yl 2-chloropropionate, 3-methyl 2-chloropropionate, any one of 2-chloro-3-oxypropyl ester, ethyl 2-((2-chloropropionyl)thio)acetate, ethyl 2-((2-chloropropionyl)thio)propionate, methyl 3-((2-chloropropionyl)thio)propionate, methyl 3-(2-chloropropionamido)propionate, methyl 2-chloro-2-methylpropionate, ethyl 2-chloro-2-methylpropionate, methyl 2-chlorobutyrate, ethyl 2-chlorobutyrate, methyl 2-chloro-3-methylbutyrate, and ethyl 2-chloro-3-methylbutyrate.

[0104] Another object of the present invention is to use the N-phenyl triazone derivative in the preparation of herbicides and weed growth enzyme inhibitors.

[0105] Specifically, the weeds are crabgrass, barnyard grass, ramie, Amaranthus retroflexus, quinoa, ryegrass, purslane, bermudagrass, rapeseed, veronica, amaranth, nightshade, bitter melon, dandelion, sage, clover, chickweed, Leptochloa chinensis, goosegrass, and foxtail grass.

[0106] Beneficial effects:

[0107] The invention is based on the structure of N-phenyl triazone, and optimizes and derives to create N-phenyl triazone herbicide small molecules with stable physicochemical properties and excellent drugability; the derivatives have significant post-emergence inhibitory effects on barnyard grass, goosegrass, foxtail grass, ramie, Amaranthus retroflexus and purslane.

[0108] Through the post-emergence herbicidal activity test, it was found that some N-phenylthiotriazine compounds, including compounds E3, E4, E5, E9, E10, E33, and E37, had excellent herbicidal activity against barnyard grass, goosegrass, foxtail grass, velvet, Amaranthus retroflexus, and purslane at a dosage of 150 g ai / ha. The weeds completely withered and their growth was severely inhibited, with the inhibition rate reaching 100%, which was equivalent to the positive control trifluoxetine; at a dosage of 75 g ai / ha, compounds E3, E4, E5, E9, E33, and E37 had excellent herbicidal activity against barnyard grass, crabgrass, foxtail grass, velvet, Amaranthus retroflexus, and purslane, with the inhibition rate reaching 100%.

[0109] The N-phenylthiotriazine one derivative designed and synthesized by the present invention has a simple structure and a simple preparation process, has good herbicidal activity against broad-leaved weeds and is relatively safe for broad-leaved crops, has readily available raw materials, has low production costs, has a high overall yield, is non-toxic and harmless during the preparation process, and has great application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0110] Figure 1 The following is a preparation route of the N-phenyl triazone derivatives of Examples 1 to 25;

[0111] Figure 2 The following is a preparation route for the N-phenyl triazone derivatives of Examples 26 to 40. DETAILED DESCRIPTION

[0112] The specific embodiments of the present invention are further described in detail below, but the present invention is not limited to these embodiments, and any improvement or substitution based on the basic spirit of the present embodiment still falls within the scope of protection required by the claims of the present invention.

[0113] Example 1: A method for preparing (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate (i.e., compound E1), comprising the following steps:

[0114] (1) Preparation of methyl 2-(5-amino-2-chloro-4-fluorophenoxy)propionate:

[0115] Take 1-(2-chloro-4-fluoro-5-nitrophenyl)ethan-1-one (40.00 g, 183.84 mmol), NH4Cl (29.50 g, 551.52 mmol) and EtOH (90%, 300 mL) and add them to a flask, and the mixture is heated to 80°C, and then iron powder (30.80 g, 551.52 mmol) is added to the solution in batches, and then the reaction mixture is refluxed for 4 hours; after the reaction is completed, the hot reaction mixture is filtered through a diatomaceous earth pad, the residue is washed with ethyl acetate (100 mL), H2O (200 mL) is added to the filtrate, and 200 mL of ethyl acetate is extracted, the organic layers are combined, and anhydrous Na2SO4 is dried and concentrated by rotary evaporation to obtain 26.31 g of 1-(5-amino-2-chloro-4-fluorophenyl)ethan-1-one intermediate, with a yield of 76.29%;

[0116] (2) Preparation of 3-(5-acetyl-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione:

[0117] Triphosgene (41.62 g, 140.25 mmol) was dissolved in 100 mL of toluene and added to a 500 mL round-bottom flask, and cooled to 0°C. Methyl 2-(5-amino-2-chloro-4-fluorophenoxy)propanoate (26.31 g, 140.25 mmol) and a solution of Et3N (2.84 g, 28.25 mmol) dissolved in 100 mL of toluene were added dropwise over 10 minutes, and the mixture was slowly heated to reflux for 10 hours, cooled to room temperature, and the solvent was removed by rotary evaporation. Toluene (200 mL) and CS(NHCH3)2 (29.22 g, 280.49 mmol) were added to the residue in sequence, and the solution was added to the flask. The mixture was stirred at room temperature for 30 minutes, and then CDI (45.48 g, 280.49 mmol) was added to the solution, and the solution was slowly heated to 85°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and ethyl acetate (200 mL) and H2O (200 mL) were added to the solution. The organic layer was separated, washed with H2O (200 mL) and saturated NaCl solution (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. 31.07 g of 3-(5-acetyl-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione intermediate was obtained by column chromatography with a yield of 64.45%.

[0118] (3) Preparation of (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione:

[0119] 3-(5-acetyl-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (15.00 g, 43.64 mmol), hydroxylamine hydrochloride (6.06 g, 87.27 mmol) and EtOH (80%, 100 mL) were added to a flask, and the mixture was heated to 80° C., and then the reaction mixture was refluxed for 4 hours; after the reaction was completed, it was extracted with 200 mL of ethyl acetate and 200 mL of water, the organic layers were combined, and dried over anhydrous Na2SO4 by rotary evaporation and concentrated, and column chromatography was performed to obtain (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione intermediate 14.31 g, with a yield of 91.41%;

[0120] (4) Preparation of (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate:

[0121] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (200 mg, 557.46 μmol), add 10 mL DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add methyl 2-chloroacetate (175.91 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetic acid methyl ester in a yield of 81.11%.

[0122] Example 2: A method for preparing ethyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate (i.e., compound E2), comprising the following steps:

[0123] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0124] (4) Preparation of (E)-ethyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate:

[0125] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, and then add ethyl chloroacetate (85.39 mg, 696.82 μmol) , and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetic acid ethyl ester with a yield of 79.43%.

[0126] Example 3: A method for preparing (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propyl acetate (i.e., compound E3), comprising the following steps:

[0127] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0128] (4) Preparation of (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propyl acetate:

[0129] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, and then add propyl chloroacetate (95.17 mg, 696.82 μmol) , and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate in a yield of 75.83%.

[0130] Example 4: A method for preparing (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetic acid butyl ester (i.e., compound E4), comprising the following steps:

[0131] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0132] (4) Preparation of (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butyl acetate:

[0133] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, and then add butyl chloroacetate (115.56 mg, 696.82 μmol) , and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetic acid butyl ester in a yield of 73.09%.

[0134] Example 5: A method for preparing (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)pentyl acetate (i.e., compound E5), comprising the following steps:

[0135] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0136] (4) Preparation of (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate:

[0137] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, and then add amyl chloroacetate (114.72 mg, 696.82 μmol) , and then react at room temperature for 6 hours; after completion, pour it into 40 mL of water, extract the mixture with 40 mL of ethyl acetate, collect the organic layer, dry it over anhydrous Na2SO4, and concentrate under reduced pressure. The residue can be purified by column chromatography to obtain (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate in a yield of 70.64%.

[0138] Example 6: A method for preparing (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)benzyl acetate (i.e., compound E6), comprising the following steps:

[0139] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0140] (4) Preparation of (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)benzyl acetate:

[0141] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add benzyl chloroacetate (128.65 mg, 696.82 μmol), and then react at room temperature for 6 hours. After the reaction is completed, it is poured into 40 mL of water, and the mixture is extracted with 40 mL of ethyl acetate. The organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetic acid benzyl ester in a yield of 78.75%.

[0142] Example 7: A method for preparing methyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate (i.e., compound E7), comprising the following steps:

[0143] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0144] (4) Preparation of methyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate:

[0145] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add methyl 2-chloropropionate (85.39 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionic acid methyl ester with a yield of 72.67%.

[0146] Example 8: A method for preparing ethyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate (i.e., compound E8), comprising the following steps:

[0147] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0148] (4) Preparation of ethyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate:

[0149] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add ethyl 2-chloropropionate (95.17 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionic acid ethyl ester with a yield of 71.71%.

[0150] Example 9: A method for preparing (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoic acid propyl ester (i.e., compound E9), comprising the following steps:

[0151] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0152] (4) Preparation of (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoic acid propyl ester:

[0153] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add 2-chloropropionic acid propyl ester (104.94 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionic acid propyl ester with a yield of 66.80%.

[0154] Example 10: A method for preparing (E)-butyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate (i.e., compound E10), comprising the following steps:

[0155] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0156] (4) Preparation of butyl (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionate:

[0157] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add 2-chloropropionic acid butyl ester (114.72 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionic acid butyl ester, with a yield of 73.19%.

[0158] Example 11: A method for preparing (E)-pentyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate (i.e., compound E11), comprising the following steps:

[0159] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0160] (4) Preparation of (E)-pentyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate:

[0161] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add 2-chloropropionic acid pentyl ester (124.49 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionic acid pentyl ester with a yield of 71.98%.

[0162] Example 12: A method for preparing tert-butyl (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate (i.e., compound E12), comprising the following steps:

[0163] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0164] (4) Preparation of tert-butyl (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate:

[0165] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add tert-butyl 2-chloropropionate (114.72 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionic acid tert-butyl ester in a yield of 72.75%.

[0166] Example 13: A method for preparing 2-methoxy-2-oxoethyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate (i.e., compound E13), comprising the following steps:

[0167] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0168] (4) Preparation of (2-methoxy-2-oxoethyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate:

[0169] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add 2-methoxy-2-oxoethyl 2-chloropropionate (125.83 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain 2-methoxy-2-oxoethyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate in a yield of 65.46%.

[0170] Example 14: A method for preparing 1-ethoxy-1-oxopropan-2-yl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate (i.e., compound E14), comprising the following steps:

[0171] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0172] (4) Preparation of 1-ethoxy-1-oxopropan-2-yl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate:

[0173] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add 2-chloropropionic acid 1-methoxy-1-oxopropan-2-yl ester (135.61 mg, 696.82 μmol) l), and then reacted at room temperature for 6 hours; after the reaction was completed, it was poured into 40mL of water, the mixture was extracted with 40mL of ethyl acetate, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1-ethoxy-1-oxopropan-2-yl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate, with a yield of 61.36%.

[0174] Example 15: A method for preparing 3-methoxy-3-oxopropyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate (i.e., compound E15), comprising the following steps:

[0175] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0176] (4) Preparation of 3-methoxy-3-oxopropyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate:

[0177] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add 2-chloropropionic acid 3-methoxy-3-oxypropyl ester (135.61 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain 3-methoxy-3-oxopropyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate in a yield of 67.93%.

[0178] Example 16: A method for preparing ((E)-2-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)acetate (i.e., compound E16), comprising the following steps:

[0179] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0180] (4) Preparation of ((E)-2-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)acetate:

[0181] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, and then add ethyl 2-((2-chloropropionyl)thio)acetate (146.82 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain ((E)-2-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)acetate in a yield of 67.93%.

[0182] Example 17: A method for preparing (E)-2-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)propanoate (i.e., compound E17), comprising the following steps:

[0183] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0184] (4) Preparation of (E)-2-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)propanoate:

[0185] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, and then add ethyl 2-((2-chloropropionyl)thio)propionate (146.82 mg, 696.82 μmol) l), and then reacted at room temperature for 6 hours; after the reaction was completed, it was poured into 40 mL of water, the mixture was extracted with 40 mL of ethyl acetate, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain (E)-2-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)propanoate, with a yield of 57.41%.

[0186] Example 18: A method for preparing (E)-3-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)propanoate (i.e., compound E18), comprising the following steps:

[0187] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0188] (4) Preparation of (E)-3-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)propanoate:

[0189] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, and then add 3-((2-chloropropionyl)thio)propionic acid methyl ester (146.80 mg, 696.82 μmol) l), and then reacted at room temperature for 6 hours; after the reaction was completed, it was poured into 40 mL of water, the mixture was extracted with 40 mL of ethyl acetate, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain (E)-3-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)propanoate, with a yield of 60.38%.

[0190] Example 19: A method for preparing methyl (E)-3-(2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionamido)propanoate (i.e., compound E19), comprising the following steps:

[0191] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0192] (4) Preparation of (E)-3-(2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionamido)propanoic acid methyl ester:

[0193] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, and then add 3-(2-chloropropionamido)propionic acid methyl ester (134.92 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-3-(2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionamido)propionic acid methyl ester with a yield of 64.41%.

[0194] Example 20: A method for preparing (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-2-methylpropanoate (i.e., compound E20), comprising the following steps:

[0195] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0196] (4) Preparation of (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-2-methylpropanoic acid methyl ester:

[0197] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add 2-chloro-2-methylpropionic acid methyl ester (95.17 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40mL of water, the mixture is extracted with 40mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-2-methylpropanoic acid methyl ester, with a yield of 70.67%. Example 21: The preparation method of (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-2-methylpropanoic acid ester (i.e., compound E21), comprising the following steps:

[0198] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0199] (4) Preparation of (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-2-methylpropanoate:

[0200] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add ethyl 2-chloro-2-methylpropanoate (104.94 mg, 696.82 μmol) l), and then reacted at room temperature for 6 hours; after the reaction was completed, it was poured into 40mL of water, the mixture was extracted with 40mL of ethyl acetate, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-2-methylpropanoate, with a yield of 70.01%. Example 22: The preparation method of (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butyric acid methyl ester (i.e., compound E22), comprising the following steps:

[0201] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0202] (4) Preparation of (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butanoate:

[0203] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add methyl 2-chlorobutyrate (95.17 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butyric acid methyl ester in a yield of 74.19%.

[0204] Example 23: A method for preparing ethyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butanoate (i.e., compound E23), comprising the following steps:

[0205] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0206] (4) Preparation of ethyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butyrate:

[0207] Take (E)-3-(4-chloro-2-fluoro-5-(1-(hydroxyimino)ethyl)phenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, then add ethyl 2-chlorobutyrate (104.94 mg, 696.82 μmol) ), and then react at room temperature for 6 hours; after the reaction is completed, it is poured into 40 mL of water, the mixture is extracted with 40 mL of ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butyric acid ethyl ester in a yield of 73.67%.

[0208] Example 24: A method for preparing (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoate (i.e., compound E24), comprising the following steps:

[0209] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0210] (4) Preparation of (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoic acid methyl ester:

[0211] Take (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoic acid methyl ester (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, and then add 2-chloro-3-methylbutanoic acid methyl ester (104.94 mg, 696.82 μmol), and then reacted at room temperature for 6 hours; after the reaction was completed, it was poured into 40 mL of water, the mixture was extracted with 40 mL of ethyl acetate, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butyric acid methyl ester in a yield of 67.46%.

[0212] Example 25: A method for preparing (E)-ethyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoate (i.e., compound E25), comprising the following steps:

[0213] Steps (1)-(3): same as steps (1)-(3) of Example 1;

[0214] (4) Preparation of (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoic acid ethyl ester:

[0215] Take (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoic acid methyl ester (250 mg, 557.46 μmol), add 10 mL of DMF to dissolve, add potassium carbonate (115.26 mg, 836.18 μmol), stir at room temperature for 30 min, and then add 2-chloro-3-methylbutanoic acid ethyl ester (114.72 mg, 69 6.82 μmol), and then reacted at room temperature for 6 hours; after the reaction was completed, it was poured into 40 mL of water, the mixture was extracted with 40 mL of ethyl acetate, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoic acid ethyl ester in a yield of 66.84%.

[0216] Example 26: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester (i.e., Compound E26), comprising the following steps:

[0217] Steps (1)-(2): the same as steps (1)-(2) of Example 1;

[0218] (3) Preparation of 3-(5-(2-bromoacetyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione:

[0219] Take 3-(5-acetyl-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (15 g, 43.64 mmol), add 100 mL 30% HBr (in acetic acid) to dissolve, then add Br2 (7.67 g, 48 mmol), and then react in an ice bath for 1 hour; after the reaction is completed, pour it into 200 mL ice water, the mixture is extracted with 200 mL ethyl acetate, the organic layer is collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue can be obtained by column chromatography to obtain 3-(5-(2-bromoacetyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione, with a yield of 73.09%;

[0220] (4) Preparation of (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione:

[0221] Take 3-(5-(2-bromoacetyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione (13.48 g, 31.89 mmol), hydroxylamine hydrochloride (4.43 g, 63.79 mmol), add 100 mL of 80% ethanol to dissolve and then reflux for 4 hours; after the reaction is completed, pour it into 100 mL of water, extract the mixture with 100 mL of ethyl acetate, collect the organic layer, dry it with anhydrous Na2SO4, and concentrate under reduced pressure. The residue can be obtained by column chromatography to obtain (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thio-1,3,5-triazinane-2,4-dione, with a yield of 85.04%;

[0222] (5) Preparation of methyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-5,6-dihydro-4H-1,2-oxazine-6-carboxylate:

[0223] Take (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), methyl acrylate (49.18 mg, 571.21 μmol) Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate and add them to the calcined water. bottle and stirred at room temperature for 6 hours. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water, the organic layers were combined, and dried over anhydrous Na2SO4 and concentrated by rotary evaporation. 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester was obtained by column chromatography with a yield of 64.37%.

[0224] Example 27: A method for preparing ethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-5,6-dihydro-4H-1,2-oxazine-6-carboxylate (i.e., compound E27), comprising the following steps:

[0225] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0226] (5) Preparation of methyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-5,6-dihydro-4H-1,2-oxazine-6-carboxylate:

[0227] Take (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), ethyl acrylate (49.18 mg, 571.21 μmol) Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate and add them to the calcined water. bottle and stirred at room temperature for 6 hours. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water, the organic layers were combined, and dried over anhydrous Na2SO4 and concentrated by rotary evaporation. 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester was obtained by column chromatography with a yield of 61.23%.

[0228] Example 28: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-fluoro-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester (i.e., Compound E28), comprising the following steps:

[0229] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0230] (5) Preparation of methyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-fluoro-5,6-dihydro-4H-1,2-oxazine-6-carboxylate:

[0231] Take (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), methyl 2-fluoroacrylate (59.45 mg, 571.21 μmol) Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate and add them to a flask. , stirred at room temperature for 6 hours; after the reaction was completed, extracted with 20 mL of ethyl acetate and 20 mL of water, the organic layers were combined, dried over anhydrous Na2SO4 and concentrated by rotary evaporation, and column chromatography was performed to obtain 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-fluoro-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester in a yield of 58.39%.

[0232] Example 29: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester (i.e., Compound E29), comprising the following steps:

[0233] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0234] (5) Preparation of methyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate:

[0235] (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), methyl methacrylate (59.17 mg, 571.21 μmol), Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate were added to a flask. The mixture was stirred at room temperature for 6 h. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layers were combined and concentrated by rotary evaporation over anhydrous Na2SO4. Column chromatography gave 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester in a yield of 58.39%.

[0236] Example 30: A method for preparing ethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate (i.e., compound E30), comprising the following steps:

[0237] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0238] (5) Preparation of ethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate:

[0239] (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), ethyl methacrylate (65.20 mg, 571.21 μmol), Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate were added to a flask. The mixture was stirred at room temperature for 6 h. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layers were combined and concentrated by rotary evaporation over anhydrous Na2SO4. 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid ethyl ester was obtained by column chromatography in a yield of 59.75%.

[0240] Example 31: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid propyl ester (i.e., Compound E31), comprising the following steps:

[0241] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0242] (5) Preparation of 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid propyl ester:

[0243] (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), propyl methacrylate (73.21 mg, 571.21 μmol), Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate were added to a flask. The mixture was stirred at room temperature for 6 h. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layers were combined and concentrated by rotary evaporation over anhydrous Na2SO4. 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid propyl ester was obtained by column chromatography in a yield of 59.91%.

[0244] Example 32: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid butyl ester (i.e., Compound E32), comprising the following steps:

[0245] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0246] (5) Preparation of 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid butyl ester:

[0247] (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), butyl methacrylate (81.22 mg, 571.21 μmol), Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate were added to a flask. The mixture was stirred at room temperature for 6 h. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layers were combined and concentrated by rotary evaporation over anhydrous Na2SO4. 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid butyl ester was obtained by column chromatography in a yield of 61.69%.

[0248] Example 33: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid isopropyl ester (i.e., Compound E33), comprising the following steps:

[0249] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0250] (5) Preparation of 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid isopropyl ester:

[0251] Take (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), isopropyl methacrylate (73.21 mg, 571.21 μmol), Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate and add them to a flask and stir at room temperature for 6 h. After the reaction was completed, the mixture was extracted with 20 mL of ethyl acetate and 20 mL of water, the organic layers were combined, and the mixture was concentrated by rotary evaporation over anhydrous Na2SO4. 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid isopropyl ester was obtained by column chromatography in a yield of 56.93%.

[0252] Example 34: A method for preparing tert-butyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate (i.e., Compound E34), comprising the following steps:

[0253] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0254] (5) Preparation of tert-butyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate:

[0255] (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), tert-butyl methacrylate (81.22 mg, 571.21 μmol), Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate were added to a flask. The mixture was stirred at room temperature for 6 h. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layers were combined and concentrated by rotary evaporation over anhydrous Na2SO4. 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid tert-butyl ester was obtained by column chromatography in a yield of 56.78%.

[0256] Example 35: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid isobutyl ester (i.e., Compound E35), comprising the following steps:

[0257] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0258] (5) Preparation of tert-isobutyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate:

[0259] (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), isobutyl methacrylate (81.22 mg, 571.21 μmol), Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate were added to a flask. The mixture was stirred at room temperature for 6 h. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layers were combined and concentrated by rotary evaporation over anhydrous Na2SO4. 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid isobutyl ester was obtained by column chromatography in a yield of 63.55%.

[0260] Example 36: A method for preparing 2,2,2-trifluoroethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate (i.e., Compound E36), comprising the following steps:

[0261] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0262] (5) Preparation of 2,2,2-trifluoroethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate:

[0263] (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), 2,2,2-trifluoroethyl methacrylate (96.03 mg, 571.21 μmol), Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate were added to a flask. The mixture was stirred at room temperature for 6 h. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layers were combined and concentrated by rotary evaporation over anhydrous Na2SO4. 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid 2,2,2-trifluoroethyl ester was obtained by column chromatography in a yield of 61.31%.

[0264] Example 37: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid cyclohexyl ester (i.e., Compound E37), comprising the following steps:

[0265] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0266] (5) Preparation of 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid cyclohexyl ester:

[0267] (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), cyclohexyl methacrylate (96.10 mg, 571.21 μmol), Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate were added to a flask. The mixture was stirred at room temperature for 6 h. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layers were combined and concentrated by rotary evaporation over anhydrous Na2SO4. 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid cyclohexyl ester was obtained by column chromatography in a yield of 55.28%.

[0268] Example 38: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid benzyl ester (i.e., Compound E38), comprising the following steps:

[0269] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0270] (5) Preparation of 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid benzyl ester:

[0271] Take (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), benzyl methacrylate (100.66 mg, 571.21 μmol) Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate and add them to a flask. , stirred at room temperature for 6 hours; after the reaction was completed, extracted with 20 mL of ethyl acetate and 20 mL of water, the organic layers were combined, dried over anhydrous Na2SO4 and concentrated by rotary evaporation, and column chromatography was performed to obtain 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid benzyl ester in a yield of 58.74%.

[0272] Example 39: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid oxirane-2-ylmethyl ester (i.e., Compound E39), comprising the following steps:

[0273] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0274] (5) Preparation of 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid oxirane-2-ylmethyl ester:

[0275] Take (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), methacrylate-2-oxirane methyl ester (81.20 mg, 571.21 μmol) Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate and add them to a flask. , stirred at room temperature for 6 hours; after the reaction was completed, extracted with 20 mL of ethyl acetate and 20 mL of water, the organic layers were combined, dried over anhydrous Na2SO4 and concentrated by rotary evaporation, and column chromatography was used to obtain 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid oxirane-2-ylmethyl ester in a yield of 56.14%.

[0276] Example 40: A method for preparing 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid (tetrahydrofuran-2-yl)methyl ester (i.e., Compound E40), comprising the following steps:

[0277] Steps (1)-(4): same as steps (1)-(4) of Example 26;

[0278] (5) Preparation of 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid (tetrahydrofuran-2-yl) methyl ester:

[0279] (E)-3-(5-(2-bromo-1-(hydroxyimino)ethyl)-4-chloro-2-fluorophenyl)-1,5-dimethyl-6-thioxo-1,3,5-triazinane-2,4-dione (200 mg, 456.97 μmol), methyl methacrylate (tetrahydrofuran-2-yl) methyl ester (97.22 mg, 571.21 μmol), Na2CO3 (72.65 mg, 685.45 μmol) and ethyl acetate were added to a flask. The mixture was stirred at room temperature for 6 h. After the reaction was completed, it was extracted with 20 mL of ethyl acetate and 20 mL of water. The organic layers were combined and concentrated by rotary evaporation over anhydrous Na2SO4. Column chromatography gave 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazine-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid (tetrahydrofuran-2-yl) methyl ester in a yield of 67.41%.

[0280] The structural formula and molecular formula of the target compound prepared in the above examples are shown in Table 1, and its physicochemical properties and spectral information are shown in Table 1;

[0281] Table 1 Molecular formula and structural formula of the target compound obtained in Examples 1-40

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288] Table 2 Spectral data of target compounds obtained in Examples 1-40

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297] Post-emergence activity test of target compounds: This test adopts the spray method, with a variety of weeds as the test objects. Weed seeds are directly sown and evenly spread in 8x 8cm plastic pots filled with two-thirds organic matrix soil, and placed in a greenhouse for growth. When both grass weeds and broadleaf weeds grow to the two- to three-leaf stage, they can be used for testing. The compound is dissolved in 100μLDMF and diluted to a dose of 37.5–150g ai / ha with 0.1% Tween-80. Trifluoxetine is used as a positive control and the target compound to spray all weeds. After the treated weeds are placed in the greenhouse for 15 days, their herbicidal activity is evaluated by visual inspection against the CK group, and repeated three times.

[0298] Table 3 Post-emergence herbicidal activity of target compounds of Examples 1-40

[0299]

[0300]

[0301]

[0302]

[0303] It can be seen from Table 3 that at a dosage of 150 g ai / ha, compounds E3, E4, E5, E9, E10, E33, and E37 have excellent herbicidal activity against barnyard grass, crabgrass, Setaria viridis, velvet, Amaranthus retroflexus, and Portulaca oleracea. The weeds were completely withered and their growth was severely inhibited. The inhibition rates all reached 100%, which was equivalent to the positive control trifluoxetine. At a dosage of 75 g ai / ha, compounds E3, E4, E5, E9, E33, and E37 had excellent herbicidal activity against barnyard grass, crabgrass, Setaria viridis, velvet, Amaranthus retroflexus, and Portulaca oleracea, and the inhibition rates all reached 100%.

[0304] Crop safety test of target compound: This test adopts the spray method, with six typical substances as the test objects, directly sowing crop seeds, evenly spreading them in 8x8cm plastic pots filled with two-thirds organic matrix soil, and growing them in a greenhouse. The compound was dissolved in 100μL DMF and diluted to a dose of 150g ai / ha with 0.1% Tween-80. Trifluoxetine was used as a positive control and the target compound to spray all weeds. After the treated crops were placed in the greenhouse for 30 days, the crop safety was evaluated by visual inspection against the CK group, and repeated three times.

[0305] Table 4 Crop safety of target compounds of Examples 4 and 9 at a dose of 150 g ai / ha

[0306]

[0307] As can be seen from Table 4, trifluoxetine caused very serious damage to several typical crops, and even caused complete death of the plants. Compounds E4 and E9 at a dosage of 150 g ai / ha showed good crop safety to crops such as rice, corn, wheat, peanuts, soybeans, and cotton (40-50%), while trifluoxetine caused complete death of peanut, soybean, and cotton plants, and the phytotoxicity was very serious.

[0308] In summary, this series of N-phenyl triazone derivatives has novel structure, readily available raw materials, simple preparation process, and some compounds also have excellent post-emergence herbicidal activity and good crop safety. Therefore, this series of compounds has great potential to become PPO inhibitors, post-emergence herbicides, and selective herbicides are further developed, so that they can be applied to more farmlands.

[0309] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the technical solution of the present invention still falls within the scope of the technical solution of the present invention.

Claims

1. An N-phenyl triazone derivative, characterized in that The general structural formula of the N-phenyl triazone derivative is as follows: In formula (I): X 1 , X 2 , X 3 Respectively selected from O, S, NCH3, N(CH3)2, NCN or NOCH3; X 4 Selected from O, S, NR 11 ONCR 8 , R 1 , R 2 are respectively selected from C1-C6 alkyl or C1-C6 haloalkyl; R 3 , R 4 are respectively selected from H, halogen, -CN, C1-C6 alkyl, (C1-C6 haloalkyl)-O- or (C1-C6 alkyl)-SO2-; R 5 are respectively selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy; R 6 are respectively selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy; R 7 are respectively selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy; R 8 are respectively selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy; R 9 are respectively selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 cyano; R 10 are selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 cyano, (CH2)nCOX 5 R 11 ; n is selected from 0, 1, 2, 3, 4, 5, and 6 respectively; X 4 Selected from O, S, NR 12 ONCR 13 ; R 11 are respectively selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C4 alkoxy C1-C6-alkyl, C1-C4 haloalkoxy C1-C6 alkyl; R 12 are respectively selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C4 alkoxy C1-C6-alkyl, C1-C4 haloalkoxy C1-C6 alkyl; R 13 They are respectively selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkynyl, C1-C4 alkoxy C1-C6-alkyl, C1-C4 haloalkoxy C1-C6 alkyl.

2. The N-phenyl triazone derivative according to claim 1, characterized in that Includes the following compounds: Compound E1: (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate; Compound E2: (E)-ethyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate; Compound E3: (E)-2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate; Compound E4: (E)-butyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate; Compound E5: (E)-pentyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate; Compound E6: (E)-benzyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)acetate; Compound E7: (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate; Compound E8: (E)-ethyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate; Compound E9: (E)-propyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate; Compound E10: (E)-butyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate; Compound E11: (E)-pentyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate; Compound E12: (E)-tert-butyl 2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate; Compound E13: 2-methoxy-2-oxoethyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate; Compound E14: 1-ethoxy-1-oxopropan-2-yl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate; Compound E15: 3-methoxy-3-oxopropyl (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoate; Compound E16: ((E)-2-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)acetate; Compound E17: (E)-2-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)propanoate; Compound E18: (E)-3-((2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propanoyl)thio)propanoate; Compound E19: (E)-methyl 3-(2-(((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)propionamido)propanoate; Compound E20: (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-2-methylpropanoate; Compound E21: (E)-2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-2-methylpropanoate; Compound E22: (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butanoate; Compound E23: (E)-ethyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)butanoate Compound E24: (E)-methyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoate; Compound E25: (E)-ethyl 2-((1-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)ethylidene)amino)oxy)-3-methylbutanoate; Compound E26: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester; Compound E27: ethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-5,6-dihydro-4H-1,2-oxazine-6-carboxylate; Compound E28: methyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-fluoro-5,6-dihydro-4H-1,2-oxazine-6-carboxylate; Compound E29: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid methyl ester; Compound E30: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid ethyl ester; Compound E31: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid propyl ester; Compound E32: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid butyl ester; Compound E33: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid isopropyl ester; Compound E34: tert-butyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate; Compound E35: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid isobutyl ester; Compound E36: ​​2,2,2-trifluoroethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylate; Compound E37: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid cyclohexyl ester; Compound E38: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid benzyl ester; Compound E39: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid oxirane-2-ylmethyl ester; Compound E40: 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazin-1-yl)-4-fluorophenyl)-6-methyl-5,6-dihydro-4H-1,2-oxazine-6-carboxylic acid (tetrahydrofuran-2-yl)methyl ester.

3. The method for preparing the N-phenyl triazone derivative according to any one of claims 1 to 2, characterized in that: The steps include: (1) Preparation of intermediate 2: Take intermediate 1, ammonium chloride and 90% ethanol solution, mix and stir, heat to 80°C, then slowly add iron powder, make the reaction system react at 80°C for 4 hours, remove the remaining iron powder by suction filtration, and then extract, dry and column chromatography to obtain intermediate 2; intermediate 1 is substituted m-nitroacetophenone; (2) Preparation of intermediate 3: Triphosgene and toluene were added to a round-bottom flask and cooled to 0°C; intermediate 2 and triethylamine were added dropwise to the flask within 10 minutes, and the mixture was slowly heated to reflux; after 10 hours, the mixture was cooled to room temperature and the solvent was removed to obtain intermediate 3; (3) Preparation of intermediate 4: Toluene and N,N-dimethylthiourea are added to the intermediate 3, and then the solution is stirred at room temperature for 30 minutes; finally, CDI is added to the solution, and the solution is slowly heated to 85°C for 12 hours; after the reaction is completed, the reaction solution is cooled to room temperature, and then concentrated under reduced pressure, extracted, separated from the organic layer, washed, dried, concentrated, and column chromatographed to obtain the intermediate 4; (4) Preparation of intermediate 5: The intermediate 4 was dissolved in 80% ethanol, hydroxylamine hydrochloride was added, and the temperature was raised to 80°C for reaction for 4 hours; after the reaction was completed, the reaction solution was cooled to room temperature, and the intermediate 5 was obtained by extraction, separation of organic layer, washing, drying, concentration, and column chromatography; (6) Preparation of intermediate 7: The intermediate 4 was dissolved in 30% HBr, and then Br2 was added dropwise in an ice bath, and stirred for 1 h in an ice bath. After the reaction was completed, it was poured into ice water, and then extracted, dried, and column chromatographed to obtain the intermediate 7; (7) Preparation of intermediate 8: The intermediate 7 was dissolved in 80% ethanol, hydroxylamine hydrochloride was added, and the temperature was raised to 80°C for reaction for 4 hours; after the reaction was completed, the reaction solution was cooled to room temperature, and the intermediate 8 was obtained by extraction, separation of organic layer, washing, drying, concentration, and column chromatography; (8) Preparation of target compounds E1-E25: The intermediate 5 is dissolved in DMF, potassium carbonate and the intermediate 6 are added, and the mixture is stirred at room temperature. After the reaction is completed, the N-phenyl triazone derivatives E1-E25 are obtained after extraction, separation of the organic layer, drying, and column chromatography. The intermediate 6 is a substituted 2-chlorocarboxylic acid derivative. (9) Preparation of target compounds E26–E40: The intermediate 8 was dissolved in ethyl acetate, and sodium carbonate and a substituted enoic acid derivative were added. The mixture was stirred at room temperature. After the reaction was completed, the N-phenyl triazone derivatives E26–E40 were obtained after extraction, separation of the organic layer, drying, and column chromatography.

4. The method for preparing the N-phenyl triazone derivative according to claim 3, characterized in that: The substituted m-nitroacetophenone is 1-(2-chloro-4-fluoro-5-nitrophenyl)ethan-1-one.

5. The method for preparing the N-phenyl triazone derivative according to claim 3, characterized in that: The substituted 2-chlorocarboxylic acid derivatives are methyl 2-chloroacetate, ethyl chloroacetate, propyl chloroacetate, butyl chloroacetate, pentyl chloroacetate, benzyl chloroacetate, methyl 2-chloropropionate, ethyl 2-chloropropionate, propyl 2-chloropropionate, butyl 2-chloropropionate, pentyl 2-chloropropionate, tert-butyl 2-chloropropionate, 2-methoxy-2-oxoethyl 2-chloropropionate, 1-methoxy-1-oxopropan-2-yl 2-chloropropionate, 3-methoxy-2-chloropropionate, any one of 2-chloro-3-methylbutyrate, ethyl 2-((2-chloropropionyl)thio)propionate, ethyl 2-((2-chloropropionyl)thio)propionate, methyl 3-((2-chloropropionyl)thio)propionate, methyl 3-(2-chloropropionamido)propionate, methyl 2-chloro-2-methylpropionate, ethyl 2-chloro-2-methylpropionate, methyl 2-chlorobutyrate, ethyl 2-chlorobutyrate, methyl 2-chloro-3-methylbutyrate, and ethyl 2-chloro-3-methylbutyrate.

6. Use of the N-phenylthiotriazine derivative as claimed in claim 1 or 2 in the preparation of weed control and weed growth enzyme inhibitors.

7. The use of N-phenylthiotriazineone in preparing weed control as claimed in claim 6, characterized in that: The weeds are crabgrass, barnyard grass, ramie, amaranth, quinoa, ryegrass, purslane, bermudagrass, rapeseed, veronica, amaranth, nightshade, bitter melon, dandelion, sage, clover, chickweed, lycopodiella, goosegrass, and foxtail grass.

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