N-phenylimine derivative, preparation method and application thereof

Abstract

The present invention belongs to the technical field of chemical industry and pesticide, and specifically relates to a derivative containing N-phenylimine, a preparation method thereof and an application thereof. The present invention provides a derivative containing N-phenylimine, including: a 1,2,4-oxadiazole-N-phenylimine derivative with a structure shown in Formula 1, a 1,3,4-oxadiazole-N-phenylimine derivative with a structure shown in Formula 2, an N-phenylimine amide (ester) derivative with a structure shown in Formula 3 or an N-phenylimine benzoate derivative with a structure shown in Formula 4. The N-phenylimine derivative provided by the present invention has a 100% inhibitory effect on broad-leaved weeds at a dose of 10a.ig / mu, and even at a dose of 2.5aig / mu, some compounds still have a 100% inhibitory effect on broad-leaved weeds. The compound provided by the present invention can be developed and used as a potential PPO inhibitor and post-emergence herbicide for broad-leaved weeds. It has a simple structure and broad application prospects. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the technical field of chemical industry and pesticide, and particularly relates to an N-phenylimine derivative, a preparation method and application thereof. Background Art

[0002] During the growing season, weeds compete with crops for water, nutrients, light, and space. If weeds are not controlled, crop yield losses can be as high as 50%. Since the mid-20th century, synthetic organic herbicides have played an important role in weed control. However, the overuse of some herbicides has led to the significant development of weed resistance and significant negative environmental impacts. Therefore, there is an urgent need to design effective, selective, environmentally friendly, and cost-effective herbicides that can limit a wide range of weeds while being environmentally friendly.

[0003] Protoporphyrinogen oxidase (PPO) is one of the most important target enzymes. It is the penultimate enzyme in chlorophyll and heme biosynthesis and belongs to a large family of enzymes containing flavonoid adenine dinucleotide (FAD). PPO catalyzes the conversion of protoporphyrinogen IX to protoporphyrin IX. PPO inhibitors can inhibit PPO in plants. This inhibition can lead to the toxic accumulation of protoporphyrin IX in the plant cytoplasm. Under light, protoporphyrin IX reacts with oxygen to produce a large amount of reactive oxygen species, which damages cell membranes and causes rapid plant burn symptoms. PPO inhibitors also offer many advantages, including a broad herbicidal spectrum, strong drug resistance, environmental friendliness, low toxicity, and low usage rates.

[0004] To date, PPO herbicides are primarily categorized into diphenyl ethers, pyrazoles, thiadiazoles, pyrimidinediones, oxazolinones, triazolinones, oxadiazoles, N-phenylphthalimides, and others. N-phenylimide inhibitors, due to their hydrophobic groups, are more readily absorbed by leaves and transported throughout the plant. Furthermore, they enhance their binding affinity with plant PPOs, offering a broader range of applications.

[0005] However, at present, the inhibitory effect of N-phenylimine inhibitors on broadleaf weeds is poor and they cannot effectively inhibit broadleaf weeds. Summary of the Invention

[0006] The present invention provides an N-phenylimine derivative, a preparation method, and applications thereof. The target compound is synthesized through cyclization, nitration, amination, and etherification, with high yield, readily available raw materials, and low cost. The N-phenylimine derivative provided by the present invention exhibits a high inhibitory effect against broadleaf weeds (such as velvetleaf, Amaranthus retroflexus, and Portulaca oleracea) at a dose of 10 μg / mu, and has broad application prospects.

[0007] The present invention provides an N-phenylimine derivative, including: a 1,2,4-oxadiazole-N-phenylimine derivative with a structure shown in Formula 1, a 1,3,4-oxadiazole-N-phenylimine derivative with a structure shown in Formula 2, an N-phenylimine amide (ester) derivative with a structure shown in Formula 3, or an N-phenylimine benzoate derivative with a structure shown in Formula 4. The present invention introduces oxadiazole, amide, ester, and phenoxyethyl structures into N-phenylimine compounds, uses different phthalimide derivatives as core skeletons, and introduces oxadiazole, amide, ester, and phenoxyethyl structural active units based on the active substructure splicing principle to synthesize a series of N-phenylphthalimide derivatives shown in Formula 1, Formula 2, Formula 3, or Formula 4; based on the phthalimide structure, the present invention uses differently substituted "imines" as pharmacophores to create a simple structure and excellent herbicidal activity. N-phenylimine herbicide; the N-phenylimine derivative provided by the present invention has an inhibitory effect of 28% to 50% on barnyard grass after seedling emergence at a drug dosage of 10a.ig / mu; an inhibitory effect of 34% to 56% on crabgrass after seedling emergence; an inhibitory effect of 50% to 70% on foxtail grass after seedling emergence; an inhibitory effect of 100% on velvetleaf after seedling emergence; an inhibitory effect of 100% on purslane after seedling emergence; and an inhibitory effect of 100% on Amaranthus retroflexus after seedling emergence. Among them, the control agent fluazifop-butyl 10a.ig / mu has a post-emergence inhibition rate of 40-90% on the Gramineae and a 100% control effect on broad-leaved weeds; and some compounds have a 100% control effect on velvetleaf, Amaranthus retroflexus, and Portulaca oleracea at 2.5a.ig / mu, indicating that the N-phenylimine derivatives provided by the present invention have excellent control effects on broad-leaved weeds; provide a feasibility basis for the creation of high-efficiency, broad-spectrum, green, and low-toxic herbicides, and provide a potential lead structure for the development of new PPO inhibitors.

[0008] The present invention provides a method for preparing the N-phenylimine derivatives described in the above technical solution. The preparation method provided by the present invention is simple to prepare, has low production cost, and has broad application prospects. DETAILED DESCRIPTION

[0009] The present invention provides an N-phenylimine derivative, including: a 1,2,4-oxadiazole-N-phenylimine derivative having a structure shown in Formula 1, a 1,3,4-oxadiazole-N-phenylimine derivative having a structure shown in Formula 2, an N-phenylimine amide (ester) derivative having a structure shown in Formula 3, or an N-phenylimine benzoate derivative having a structure shown in Formula 4;

[0010]

[0011] In Formula 1, Formula 2, Formula 3 and Formula 4, the Het group includes:

[0012]

[0013]

[0014] In Formula 1, Formula 2, Formula 3 and Formula 4, X1 and X2 are independently F, Cl, H, Br, -CN, methyl, carboxyl, aldehyde, hydroxyl, ester or amide;

[0015] R in Formula 1 1 is H or -CH3; R in Formula 1 is a substituted aliphatic hydrocarbon group, a substituted or unsubstituted phenyl group, a substituted pyridyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group or an ester group;

[0016] R in Formula 2 3 is H or -CH3; R in Formula 2 is a substituted aliphatic hydrocarbon group, a substituted phenyl group, a substituted pyridyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group or an ester group;

[0017] In Formula 3 and Formula 4, the A is independently -NH-, -O- or -S-;

[0018] R in Formula 3 5 is an ester group, a substituted phenoxyethyl group, a substituted amine group or a substituted alkyl group;

[0019] R in Formula 4 6 It is an ester group, a substituted phenoxyethyl group, or a substituted amine group.

[0020] In the present invention, in Formula 1, Formula 2, Formula 3 and Formula 4, the Het group is preferably:

[0021] In the present invention, in Formula 1, Formula 2, Formula 3 and Formula 4, X1 and X2 are independently preferably F or Cl. In the present invention, the X1 is preferably F, and the X2 is preferably Cl.

[0022] In the present invention, R in Formula 1 1 Preferably, it is H. In the present invention, R in Formula 1 is preferably

[0023] In the present invention, R in Formula 2 3 Preferably H, in the present invention, R in Formula 2 is preferably

[0024] In the present invention, in Formula 3, A is preferably -NH- or O.

[0025] In the present invention, R in Formula 3 5 Preferably

[0026] In the present invention, in Formula 4, A is preferably O.

[0027] In the present invention, R in Formula 4 6 Preferably

[0028] In the present invention, the N-phenylimine derivatives preferably include any one of Formulas 1-1 to 1-40, 2-1 to 2-20, 3-1 to 3-35, and 4-1 to 4-2:

[0029]

[0030]

[0031]

[0032]

[0033] In the present invention, the chemical names of the compounds of Formulas 1-1 to 1-40, 2-1 to 2-20, 3-1 to 3-35, and 4-1 to 4-2 are specifically:

[0034] Compound A1: 2-(5-((3-(5-bromo-2-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0035] Compound A2: 2-(4-chloro-2-fluoro-5-((3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0036] Compound A3: 2-(4-chloro-5-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0037] Compound A4: 2-(5-(3-(2-bromophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0038] Compound A5: 2-(4-chloro-5-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0039] Compound A6: 2-(4-chloro-5-(3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0040] Compound A7: 2-(4-chloro-5-(3-(4-chloro-2-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0041] Compound A8: 2-(4-chloro-5-(3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0042] Compound A9: 2-(4-chloro-2-fluoro-5-(3-(2-fluoro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0043] Compound A10: 2-(4-chloro-5-(3-(4-chloro-6-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0044] Compound A11: 2-(4-chloro-5-(3-(2,4-dibromophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0045] Compound A12: 2-(4-chloro-2-fluoro-5-(3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0046] Compound A13: 2-(3-(3-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0047] Compound A14: 2-(4-chloro-5-(3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0048] Compound A15: 2-(4-chloro-5-(3-(2-chloro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0049] Compound A16: 2-(4-chloro-5-(3-(2,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0050] Compound A17: 2-(4-chloro-2-fluoro-5-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0051] Compound A18: 2-(4-chloro-2-fluoro-5-(3-(2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0052] Compound A19: 2-(4-chloro-2-fluoro-5-(3-(thiophen-2-yl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0053] Compound A20: 2-(4-chloro-2-fluoro-5-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0054] Compound A21: 2-(4-chloro-5-(3-(2-chloro-5-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0055] Compound A22: 2-(4-chloro-2-fluoro-5-(3-(furan-2-yl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0056] Compound A23: 2-(4-chloro-2-fluoro-5-(3-(4-fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0057] Compound A24: 2-(4-chloro-5-(3-(2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0058] Compound A25: 2-(4-chloro-2-fluoro-5-(3-phenyl-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0059] Compound A26: 2-(5-(3-(4-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0060] Compound A27: 2-(4-chloro-2-fluoro-5-(3-(4-iodophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0061] Compound B1: 2-(4-chloro-2-fluoro-5-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0062] Compound B2: 2-(4-chloro-5-((5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0063] Compound B3: 2-(4-chloro-2-fluoro-5-(5-(3-methylphenyl)-1,3,4-oxadiazole-2-methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0064] Compound B4: 2-(4-chloro-2-fluoro-5-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0065] Compound B5: 2-(4-chloro-5-(5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0066] Compound B6: 2-(5-(5-(2-bromophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0067] Compound B7: 2-(4-chloro-2-fluoro-5-(5-(2-iodophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0068] Compound B8: 2-(4-chloro-2-fluoro-5-(5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0069] Compound B9: 2-(4-chloro-2-fluoro-5-((5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0070] Compound B10: 2-(5-(5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0071] Compound B11: 2-(4-chloro-2-fluoro-5-(5-(3-iodophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0072] Compound B12: 2-(4-chloro-2-fluoro-5-(5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0073] Compound B13: 2-(4-chloro-2-fluoro-5-((5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0074] Compound B14: 2-(4-chloro-2-fluoro-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0075] Compound B15: 2-(4-chloro-5-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0076] Compound B16: 2-(4-chloro-2-fluoro-5-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0077] Compound B17: 2-(4-chloro-2-fluoro-5-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0078] Compound B18: 2-(4-chloro-2-fluoro-5-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0079] Compound B19: 2-(4-chloro-5-(5-(4-chloro-2-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0080] Compound B20: 2-(4-chloro-2-fluoro-5-(5-(2-fluoro-4-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0081] Compound C1: 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0082] Compound C2: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-methyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0083] Compound C3: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-cyanophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0084] Compound C4: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(2-fluorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0085] Compound C5: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(3,5-difluorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0086] Compound C6: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(2-methoxyphenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0087] Compound C7: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(3-fluorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0088] Compound C8: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-fluorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0089] Compound C9: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-nitrophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0090] Compound C10: 2-(4-chloro-2-fluoro-5-((4-fluorobenzyl)oxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0091] Compound C11: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-chlorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0092] Compound C12: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(2,4-difluorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0093] Compound C13: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-methoxyphenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0094] Compound C14: 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-bromophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0095] Compound C15: 2-(2-fluoro-4-(2-oxo-2-(4-methylphenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;

[0096] Compound D1: N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)acetamide;

[0097] Compound D2: 2-chloro-N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)acetamide;

[0098] Compound D3: 2-bromo-N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)propanamide;

[0099] Compound D4: 3-chloro-N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)-2,2-dimethylpropionamide;

[0100] Compound D5: (E)-N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)but-2-enamide;

[0101] Compound D6: ethyl 3-((2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)amino)-3-oxopropanoate;

[0102] Compound D7: N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)nonamide;

[0103] Compound D8: N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)cyclopropanecarboxamide;

[0104] Compound D9: N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)cyclobutanecarboxamide;

[0105] Compound D10: N-(2-chloro-5-(1,3-dioxy-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)cyclohexanecarboxamide;

[0106] Compound E1: 2-(4-chlorophenyl)-2-oxoethyl-2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorobenzoate;

[0107] Compound E2: 2-oxo-2-phenethyl-2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorobenzoate.

[0108] The present invention provides a method for preparing the N-phenylimine derivatives described in the above technical solution.

[0109] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well known to those skilled in the art.

[0110] The present invention mixes a compound of the structure shown in Formula 5, an alkali metal carbonate, a compound of the structure shown in Formula 6, and an organic solvent, and performs an affinity substitution reaction to obtain a 1,2,4-oxadiazole-N-phenylimine derivative of the structure shown in Formula 1;

[0111] In formula 6, X is Cl or Br;

[0112] In the present invention, when the compound of the structure represented by Formula 5 is preferably a compound of the structure represented by Formula 5-1, a compound of the structure represented by Formula 5-2, a compound of the structure represented by Formula 5-3, or a compound of the structure represented by Formula 5-4, the preparation method of the compound of the structure represented by Formula 5-1, Formula 5-2, Formula 5-3, or Formula 5-4 comprises the following steps:

[0113] Mixing the compound of formula 11, an ethanol-water solution, ammonium chloride, and iron powder, and performing a reduction reaction to obtain a compound of formula 12;

[0114] The compound represented by Formula 12, glacial acetic acid and a diketone compound are mixed and subjected to an affinity substitution reaction to obtain a compound represented by Formula 5-1, Formula 5-2, Formula 5-3 or Formula 4; the diketone compound is 4,5,6,7-tetrahydroisobenzofuran-1,3-dione, isobenzofuran-1,3-dione, 3-methylenedihydrofuran-2,5-dione or 3-methylenedihydrofuran-2,5-dione;

[0115]

[0116] The present invention mixes a compound with the structure represented by Formula 11, an ethanol-water solution, ammonium chloride, and iron powder, and performs a reduction reaction to obtain a compound with the structure represented by Formula 12. In the present invention, the volume fraction of ethanol in the ethanol-water solution is preferably 90%; the molar ratio of the compound with the structure represented by Formula 11 to ammonium chloride is preferably 52.21:156.62; and the molar ratio of the compound with the structure represented by Formula 11 to iron powder is preferably 52.21:156.62. The reaction is preferably carried out under reflux. In the present invention, the reduction reaction produces a reduction reaction liquid, which is preferably post-treated to obtain the compound with the structure represented by Formula 12. In the present invention, the post-treatment preferably includes the following steps: solid-liquid separation of the reduction reaction liquid to obtain a solid product and a liquid product; washing the solid product three times; mixing the liquid product and the washing solution and concentrating the mixture to obtain a solid product; and recrystallizing the solid product from ethanol to obtain the compound with the structure represented by Formula 12. The solid-liquid separation is preferably performed by suction filtration, which is performed while hot, and the washing is preferably performed three times with hot ethanol.

[0117] In the present invention, the compound represented by Formula 11 is preferably a compound represented by Formula 11-1:

[0118]

[0119] A compound of formula 12 is obtained. The present invention mixes the compound of formula 12, glacial acetic acid, and a diketone compound, and conducts an affinity substitution reaction to obtain a compound of formula 5-1, formula 5-2, formula 5-3, or formula 4; the diketone compound is 4,5,6,7-tetrahydroisobenzofuran-1,3-dione, isobenzofuran-1,3-dione, 3-methylenedihydrofuran-2,5-dione, or 3-methylenedihydrofuran-2,5-dione. In the present invention, the molar ratio of the compound of formula 12 to the diketone compound is preferably 43.33:47.66. The temperature of the affinity substitution reaction is preferably 100°C. In the present invention, after the affinity substitution reaction, the resulting reaction solution is preferably poured into ice water. After a large amount of solid product precipitates, the solution is filtered to obtain a compound of formula 5-1, formula 5-2, formula 5-3, or formula 5-4.

[0120] In the present invention, the compound of the structure shown in Formula 5-1 is preferably (Chemical name: 2-(4-chloro-2-fluoro-5-hydroxybenzene)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione). The reaction equation is:

[0121]

[0122] In the present invention, the compound of the structure shown in Formula 5-2 is preferably (Chemical name: 2-(4-chloro-2-fluoro-5-hydroxyphenyl)isoindole-1,3-dione). The reaction equation is:

[0123]

[0124] In the present invention, the compound of the structure shown in Formula 5-3 is preferably (Chemical name: 1-(4-chloro-2-fluoro-5-hydroxybenzene)-3-methylenepyrrolidine-2,5-dione). The reaction equation is:

[0125]

[0126] In the present invention, the compound of the structure shown in Formula 5-4 is preferably (Chemical name: 2-(4-chloro-2-fluoro-5-hydroxybenzene)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione). The reaction equation is:

[0127]

[0128] In the present invention, the method for preparing the compound of the structure shown in Formula 6 preferably comprises the following steps:

[0129] Mixing a compound of the structure represented by Formula 13, an organic solvent, and neutral hydroxylamine hydrochloride to carry out an amidoximation reaction to obtain a compound of the structure represented by Formula 14;

[0130] Mixing the compound represented by Formula 14, the compound represented by Formula 15, triethylamine, and an organic solvent, and performing a ring-forming reaction to obtain a compound represented by Formula 6;

[0131] R-CN formula 13,

[0132] The present invention mixes a compound of the structure shown in Formula 13, an organic solvent, and neutral hydroxylamine hydrochloride, and performs an amidoximation reaction to obtain a compound of the structure shown in Formula 14. In the present invention, the compound of the structure shown in Formula 13 is preferably: Compound of the structure shown. In the present invention, the organic solvent is preferably ethanol. In the present invention, the molar ratio of the compound of the structure shown in Formula 13 and neutral hydroxylamine hydrochloride is preferably 25.5:76.51. The amidoximation reaction is carried out under conditions of heating and reflux. In the present invention, the present invention preferably uses thin layer chromatography to monitor the completion of the reaction. After the amidoximation reaction is completed, the present invention preferably removes the solvent from the reaction solution and extracts it with dichloromethane, and the obtained extracted organic phase is dried and purified to obtain a compound of the structure shown in Formula 13. In the present invention, the solvent removal is preferably distillation under reduced pressure. The drying reagent is preferably anhydrous sodium sulfate. The purification is preferably recrystallization or column chromatography.

[0133] After obtaining the compound represented by Formula 14, the present invention mixes the compound represented by Formula 14, the compound represented by Formula 15, triethylamine, and an organic solvent to perform a cyclization reaction to obtain the compound represented by Formula 6. In the present invention, the compound represented by Formula 15 is preferably chloroacetyl chloride or chloropropionyl chloride. In the present invention, the organic solvent is preferably toluene, and the molar ratio of the compound represented by Formula 14 to the compound represented by Formula 15 and the compound represented by Formula 14 to the compound represented by Formula 15 is preferably 21.83:43.65:21.83. In the present invention, the cyclization reaction is preferably performed under heating and reflux. After the cyclization reaction, the present invention preferably extracts the reaction solution with ethyl acetate to obtain an extracted organic phase; the extracted organic phase is dried and concentrated, and the obtained concentrated solution is purified to obtain the compound represented by Formula 6. In the present invention, the drying agent is preferably anhydrous sodium sulfate. The purification is preferably performed by column chromatography.

[0134] In the present invention, the compound represented by Formula 6 is preferably a compound represented by Formula 6-1: (5-(Chloroethyl)-3-phenyl-1,2,4-oxadiazole derivative). The reaction equation is:

[0135]

[0136] In the present invention, the compound represented by Formula 6 is preferably a compound represented by Formula 6-2: (5-(Chloroethyl)-3-pyridine-1,2,4-oxadiazole derivative). The reaction equation is:

[0137]

[0138] In the present invention, the compound represented by Formula 6 is preferably a compound represented by Formula 6-3: (5-(Chloroethyl)-3-furan-1,2,4-oxadiazole derivative). The reaction equation is:

[0139]

[0140] In the present invention, the compound represented by Formula 6 is preferably a compound represented by Formula 6-4: (5-(Chloroethyl)-3-thiophene-1,2,4-oxadiazole derivative). The reaction equation is:

[0141]

[0142] In the present invention, the 1,2,4-oxadiazole-N-phenylimine derivatives of the structure shown in Formula 1 are preferably 2-(4-chloro-2-fluoro-5-((5-phenyl-1,2,4-oxadiazole-3-yl)methoxy)aryl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione derivatives, 2-(4-chloro-2-fluoro-5-(3-phenyl-1,2,4-oxadiazole-5-yl)methoxy)aryl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione derivatives, 1-(4-chloro-2-fluoro-5-((5-phenyl-1,2,4-oxadiazol-3-yl)methoxy)aryl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione derivative or 1-(4-chloro-2-fluoro-5-((5-phenyl-1,2,4-oxadiazol-3-yl)methoxy)aryl)-3-methylenepyrrolidine-2,5-dione derivative.

[0143] In the present invention, the preparation of 2-(4-chloro-2-fluoro-5-((5-phenyl-1,2,4-oxadiazol-3-yl)methoxy)aryl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione derivatives preferably comprises: dissolving 2-(4-chloro-2-fluoro-5-hydroxybenzene)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione in acetone at room temperature, adding The mixture was stirred with potassium carbonate for 30 minutes, and then a 1,2,4-oxadiazole derivative was added. After reflux until the reaction was complete, the mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the target compound, 2-(4-chloro-2-fluoro-5-((5-phenyl-1,2,4-oxadiazol-3-yl)methoxy)aryl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione derivative. The reaction equation is:

[0144]

[0145] In the present invention, the preparation method of the 2-(4-chloro-2-fluoro-5-(3-phenyl-1,2,4-oxadiazol-5-yl)methoxy)aryl)isoindole-1,3-dione derivative preferably comprises: dissolving 2-(4-chloro-2-fluoro-5-hydroxyphenyl)isoindole-1,3-dione in acetone at room temperature, adding potassium carbonate and stirring for 30 minutes, then adding a 1,2,4-oxadiazole derivative, refluxing until the reaction is complete, filtering to remove potassium carbonate, extracting, drying over anhydrous sodium sulfate, concentrating, and purifying on a silica gel chromatography column to obtain the target compound 2-(4-chloro-2-fluoro-5-(3-phenyl-1,2,4-oxadiazol-5-yl)methoxy)aryl)isoindole-1,3-dione derivative. The reaction equation is:

[0146]

[0147] In the present invention, the preparation method of the 2-(4-chloro-2-fluoro-5-((5-phenyl-1,2,4-oxadiazol-3-yl)methoxy)aryl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione derivative preferably comprises: dissolving 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione in acetone at room temperature; Potassium carbonate was added and stirred for 30 minutes, followed by the addition of a 1,2,4-oxadiazole derivative. After reflux until the reaction was complete, the mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the target compound, 2-(4-chloro-2-fluoro-5-((5-phenyl-1,2,4-oxadiazol-3-yl)methoxy)aryl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione derivative. The reaction equation is:

[0148]

[0149] In the present invention, the preparation method of the 1-(4-chloro-2-fluoro-5-((5-phenyl-1,2,4-oxadiazole-3-)methoxy)aryl)-3-methylenepyrrolidine-2,5-dione derivative preferably comprises: dissolving 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-methylenepyrrolidine-2,5-dione in acetone at room temperature, adding potassium carbonate and stirring for 30 minutes, then adding a 1,2,4-oxadiazole derivative, refluxing until the reaction is complete, filtering to remove potassium carbonate, extracting, drying over anhydrous sodium sulfate, concentrating, and purifying by silica gel chromatography to obtain the target compound 1-(4-chloro-2-fluoro-5-((5-phenyl-1,2,4-oxadiazole-3-)methoxy)aryl)-3-methylenepyrrolidine-2,5-dione derivative. The reaction equation is:

[0150]

[0151] The present invention mixes a compound with a structure shown in Formula 5, an alkali metal carbonate, a compound with a structure shown in Formula 7 and an organic solvent, and performs an affinity substitution reaction to obtain a 1,3,4-oxadiazole-N-phenylimine derivative with a structure shown in Formula 2.

[0152] In the present invention, the preparation method of the compound of the structure shown in Formula 7 comprises the following steps:

[0153] Mixing a compound of the structure shown in Formula 16, an alcohol solvent, and hydrazine hydrate to undergo an acylation reaction to obtain a compound of the structure shown in Formula 17;

[0154] Mixing a compound represented by Formula 17, a compound represented by Formula 18, an organic solvent, and phosphorus oxychloride, and performing a ring-forming reaction to obtain a compound represented by Formula 7;

[0155]

[0156] In the present invention, the compound of the structure shown in Formula 7 is preferably a 5-(chloroethyl)-3-phenyl-1,3,4-oxadiazole derivative, a 5-(chloroethyl)-3-pyridine-1,3,4-oxadiazole derivative, a 5-(chloroethyl)-3-furan-1,3,4-oxadiazole derivative or a 5-(chloroethyl)-3-thiophene-1,3,4-oxadiazole derivative.

[0157] In the present invention, the preparation method of the 5-(chloroethyl)-3-phenyl-1,3,4-oxadiazole derivative preferably comprises: using ethanol as a solvent for benzoic acid containing different substituents, adding concentrated sulfuric acid dropwise under an ice bath, heating to reflux, waiting for the reaction to complete, cooling, adjusting the pH to neutral, extracting with ethyl acetate, drying over anhydrous sodium sulfate, concentrating, and purifying by chromatography column to obtain ethyl benzoate containing different substituents. Then, using ethanol as a solvent for methyl benzoate containing different substituents, slowly adding hydrazine hydrate dropwise, heating to reflux, monitoring by TLC, after the reaction is completed, removing the solvent, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and purifying by chromatography column to obtain benzoyl hydrazide containing different substituents. Then, using 1,2-dichloroethane as a solvent for benzoyl hydrazide, adding chloroacetic acid and phosphorus oxychloride under an ice bath, and reflux reaction. After the reaction is completed, the system is quenched with ice water and the pH is adjusted to neutral with sodium bicarbonate. The mixture is extracted with dichloromethane, and the organic layer is dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain a 5-(chloroethyl)-3-phenyl-1,3,4-oxadiazole derivative. The reaction equation is:

[0158]

[0159] In the present invention, the preparation method of the 5-(chloroethyl)-3-pyridine-1,3,4-oxadiazole derivative preferably comprises: using ethanol as a solvent for ethyl picolinate containing different substituents, slowly adding hydrazine hydrate dropwise, heating to reflux, monitoring by TLC, and after the reaction is completed, removing the solvent, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and purifying with a chromatography column to obtain pyridine hydrazide containing different substituents. Then, pyridine hydrazide is treated with 1,2-dichloroethane as a solvent, chloroacetic acid and phosphorus oxychloride are added under an ice bath, and the reaction is refluxed. After the reaction is completed, the system is quenched with ice water, and the pH is adjusted to neutral with sodium bicarbonate, extracted with dichloromethane, and the organic layer is dried over anhydrous sodium sulfate, concentrated, and purified with a chromatography column to obtain a 5-(chloroethyl)-3-pyridyl-1,3,4-oxadiazole derivative. The reaction equation is:

[0160]

[0161] In the present invention, the preparation method of the 5-(chloroethyl)-3-furan-1,3,4-oxadiazole derivative preferably comprises: using ethanol as a solvent for ethyl furanoate containing different substituents, slowly adding hydrazine hydrate dropwise, heating to reflux, monitoring by TLC, and after the reaction is completed, removing the solvent, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and purifying with a chromatography column to obtain furanoylhydrazine containing different substituents. Then, the furanoylhydrazine is treated with 1,2-dichloroethane as a solvent, chloroacetyl chloride and phosphorus oxychloride are added under ice bath, and the reaction is refluxed. After the reaction is completed, the system is quenched with ice water, and the pH is adjusted to neutral with sodium bicarbonate, extracted with dichloromethane, and the organic layer is dried over anhydrous sodium sulfate, concentrated, and purified with a chromatography column to obtain a 5-(chloroethyl)-3-furanyl-1,3,4-oxadiazole derivative. The reaction equation is:

[0162]

[0163] In the present invention, the preparation method of the 5-(chloroethyl)-3-thiophene-1,3,4-oxadiazole derivative preferably comprises: using ethanol as a solvent for ethyl thiophenecarboxylate containing different substituents, slowly adding hydrazine hydrate, heating to reflux, monitoring by TLC, and after the reaction is completed, removing the solvent, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and purifying with a chromatography column to obtain thiophenecarboxamide containing different substituents. Then, thiophenecarboxamide is used as a solvent, chloroacetyl chloride and phosphorus oxychloride are added under ice bath, and reflux reaction is carried out. After the reaction is completed, the system is quenched with ice water, and the pH is adjusted to neutral with sodium bicarbonate, extracted with dichloromethane, and the organic layer is dried over anhydrous sodium sulfate, concentrated, and purified with a chromatography column to obtain a 5-(chloroethyl)-3-thienyl-1,3,4-oxadiazole derivative. The reaction equation is:

[0164]

[0165] In the present invention, the 1,3,4-oxadiazole-N-phenylimine derivatives of the structure shown in Formula 2 are preferably 2-(4-chloro-2-fluoro-5-((5-phenyl-1,3,4-oxadiazole-3-yl)methoxy)aryl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione derivatives, 2-(4-chloro-2-fluoro-5-(3-phenyl-1,3,4-oxadiazole-5-yl)methoxy)aryl )isoindole-1,3-dione derivatives, 2-(4-chloro-2-fluoro-5-((5-phenyl-1,3,4-oxadiazol-3-yl)methoxy)aryl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione derivatives or 1-(4-chloro-2-fluoro-5-((5-phenyl-1,3,4-oxadiazol-3-yl)methoxy)aryl)-3-methylenepyrrolidine-2,5-dione derivatives.

[0166] In the present invention, the preparation method of the 2-(4-chloro-2-fluoro-5-((5-phenyl-1,3,4-oxadiazol-3-yl)methoxy)aryl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione derivative preferably comprises: dissolving 2-(4-chloro-2-fluoro-5-hydroxybenzene)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione in acetone at room temperature, Potassium carbonate was added and stirred for 30 minutes, followed by the addition of a 1,3,4-oxadiazole derivative. The reaction was refluxed until complete, filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the target compound, 2-(4-chloro-2-fluoro-5-((5-phenyl-1,3,4-oxadiazol-3-yl)methoxy)aryl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione derivative. The reaction equation is:

[0167]

[0168] In the present invention, the preparation method of the 2-(4-chloro-2-fluoro-5-(3-phenyl-1,3,4-oxadiazol-5-yl)methoxy)aryl)isoindole-1,3-dione derivative preferably comprises: dissolving 2-(4-chloro-2-fluoro-5-hydroxyphenyl)isoindole-1,3-dione in acetone at room temperature, adding potassium carbonate and stirring for 30 minutes, then adding a 1,3,4-oxadiazole derivative, refluxing until the reaction is complete, filtering to remove potassium carbonate, extracting, drying over anhydrous sodium sulfate, concentrating, and purifying on a silica gel chromatography column to obtain the target compound 2-(4-chloro-2-fluoro-5-(3-phenyl-1,3,4-oxadiazol-5-yl)methoxy)aryl)isoindole-1,3-dione derivative. The reaction equation is:

[0169]

[0170] In the present invention, the preparation method of the 2-(4-chloro-2-fluoro-5-((5-phenyl-1,3,4-oxadiazol-3-yl)methoxy)aryl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione derivative preferably comprises: dissolving 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione in acetone at room temperature; Potassium carbonate was added and stirred for 30 minutes, followed by the addition of a 1,3,4-oxadiazole derivative. After reflux until the reaction was complete, the mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the target compound, 2-(4-chloro-2-fluoro-5-((5-phenyl-1,3,4-oxadiazol-3-yl)methoxy)aryl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione derivative. The reaction equation is:

[0171]

[0172] In the present invention, the preparation method of the 1-(4-chloro-2-fluoro-5-((5-phenyl-1,3,4-oxadiazole-3-)methoxy)aryl)-3-methylenepyrrolidine-2,5-dione derivative preferably comprises: dissolving 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-methylenepyrrolidine-2,5-dione in acetone at room temperature, adding potassium carbonate and stirring for 30 minutes, then adding a 1,3,4-oxadiazole derivative, refluxing until the reaction is complete, filtering to remove potassium carbonate, extracting, drying over anhydrous sodium sulfate, concentrating, and purifying by silica gel chromatography to obtain the target compound 1-(4-chloro-2-fluoro-5-((5-phenyl-1,3,4-oxadiazole-3-)methoxy)aryl)-3-methylenepyrrolidine-2,5-dione derivative. The reaction equation is:

[0173]

[0174] In the present invention, when A in Formula 3 is O or S: a compound represented by Formula 5, an alkali metal carbonate, a compound represented by Formula 8, and an organic solvent are mixed and subjected to an affinity substitution reaction to obtain an N-phenylimine amide (ester) derivative represented by Formula 3;

[0175] X-R5 is formula 8; X in formula 8 is Cl or Br;

[0176] In the present invention, the compound with the structure shown in Formula 8 is preferably an α-bromo(chloro)acetophenone derivative.

[0177] In the present invention, the preparation method of the α-bromo(chloro)acetophenone derivative preferably comprises: adding water as a solvent to acetophenone containing different substitutions, then stirring and heating to 90° C., slowly adding liquid bromine dropwise to the system while maintaining the temperature constant, and after the reaction is completed, cooling to room temperature, filtering, and recrystallizing to obtain the α-bromo(chloro)acetophenone derivative. The reaction equation is:

[0178] In the present invention, when A in Formula 3 is O or S, the N-phenylimine amide (ester) derivative of the structure shown in Formula 3 is preferably a 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione derivative, a 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)isoindoline-1,3-dione derivative, a 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione derivative or a 1-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)-3-methylpyrrolidine-2,5-dione derivative.

[0179] In the present invention, the preparation method of 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione derivative preferably comprises: dissolving 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione in acetonitrile at room temperature, adding potassium carbonate and stirring for 30 minutes, then adding an α-bromo(chloro)acetophenone derivative, refluxing until the reaction is complete, filtering to remove potassium carbonate, extracting, drying over anhydrous sodium sulfate, concentrating, and purifying by silica gel chromatography to obtain the target compound 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione derivative. The reaction equation is:

[0180]

[0181] In the present invention, the preparation method of 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)isoindoline-1,3-dione derivative preferably comprises: dissolving 2-(4-chloro-2-fluoro-5-hydroxyphenyl)isoindole-1,3-dione in acetonitrile at room temperature, adding potassium carbonate and stirring for 30 minutes, then adding an α-bromo(chloro)acetophenone derivative, refluxing until the reaction is complete, filtering to remove potassium carbonate, extracting, drying over anhydrous sodium sulfate, concentrating, and purifying by silica gel chromatography to obtain the target compound 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)isoindoline-1,3-dione derivative. The reaction equation is:

[0182]

[0183] In the present invention, the preparation method of 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione derivative preferably comprises: dissolving 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione in acetonitrile at room temperature, adding potassium carbonate and stirring for 30 minutes, then adding an α-bromo(chloro)acetophenone derivative, refluxing until the reaction is complete, filtering to remove potassium carbonate, extracting, drying over anhydrous sodium sulfate, concentrating, and purifying by silica gel chromatography to obtain the target compound 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione derivative. The reaction equation is:

[0184]

[0185] In the present invention, the preparation method of 1-(4-chloro-2-fluoro-5-(2-oxo-2-phenoxyethoxy)phenyl)-3-methylpyrrolidine-2,5-dione derivative preferably comprises: dissolving 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-methylpyrrolidine-2,5-dione in acetonitrile at room temperature, adding potassium carbonate and stirring for 30 minutes, then adding α-bromo(chloro)acetophenone derivative, refluxing until the reaction is complete, filtering to remove potassium carbonate, extracting, drying over anhydrous sodium sulfate, concentrating, and purifying by silica gel chromatography to obtain the target compound 1-(4-chloro-2-fluoro-5-(2-oxo-2-phenoxyethoxy)phenyl)-3-methylpyrrolidine-2,5-dione derivative. The reaction equation is:

[0186]

[0187] In the present invention, when A in Formula 3 is -NH-: a compound of the structure shown in Formula 9, an organic base, a compound of the structure shown in Formula 8, and an organic solvent are mixed and subjected to an affinity substitution reaction to obtain an N-phenylimine amide (ester) derivative of the structure shown in Formula 3;

[0188] X-R5 is represented by formula 8; X in formula 8 is Cl or Br.

[0189] In the present invention, the method for preparing the compound of the structure shown in Formula 9 preferably comprises the following steps:

[0190] The compound of formula 19, concentrated sulfuric acid (80 wt%) and concentrated nitric acid (65 wt%) are mixed and subjected to a nitration reaction to obtain a compound of formula 20;

[0191] Mixing a compound of formula 20, an ethanol-water solvent, ammonium chloride, and iron powder, and performing a reduction reaction to obtain a compound of formula 9;

[0192]

[0193] In the present invention, the compound represented by Formula 9 is preferably a compound represented by Formula 9-1:

[0194]

[0195] In the present invention, the chemical name of the compound represented by the structure of Formula 9-1 is 2-(5-amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione.

[0196] In the present invention, the method for preparing the compound of formula 9-1 preferably comprises the following steps:

[0197] (1) Dissolve 4-chloro-2-fluoroaniline in glacial acetic acid, then add 4,5,6,7-tetrahydroisobenzofuran-1,3-dione under stirring, and heat under reflux for reaction. After the reaction is completed, pour the system into ice water and stir continuously. A large amount of solid precipitates, which is filtered, and the filter cake is washed three times with saturated sodium bicarbonate solution and dried for later use. The reaction equation is:

[0198]

[0199] (2) Dissolve 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione in 80 wt% sulfuric acid, slowly add concentrated nitric acid dropwise at -15°C, and maintain the temperature until the reaction is complete. After the reaction is complete, pour the system into ice water and stir continuously. A large amount of yellow solid precipitates. Filter by suction, wash the filter cake three times with saturated sodium bicarbonate solution, and dry for later use. The reaction equation is:

[0200]

[0201] (3) 2-(4-chloro-2-fluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione was dissolved in 90 vol% ethanol, and then ammonium chloride was added. The mixture was stirred and heated to reflux reaction. Iron powder was then slowly added and the reflux reaction was continued. After the reaction was completed, the mixture was filtered, the filtrate was collected, concentrated, and recrystallized to obtain the compound 2-(5-amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione. The reaction equation is:

[0202]

[0203] In the present invention, when A in Formula 3 is -NH-, the N-phenylimine amide (ester) derivative of the structure shown in Formula 3 is preferably an N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)amide derivative.

[0204] In the present invention, the preparation method of N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)amide derivatives preferably comprises: using dichloromethane as a solvent, adding different acid chlorides and triethylamine as a catalyst under ice bath, and stirring at room temperature for reaction. After the reaction is completed, extraction is performed with ethyl acetate, drying over anhydrous sodium sulfate, and purification is performed on a silica gel chromatography column. The reaction equation is:

[0205]

[0206] In the present invention, a compound having a structure shown in Formula 10, an organic solvent and a compound containing a Het group are mixed and subjected to an affinity substitution reaction to obtain an N-phenyliminobenzoate derivative having a structure shown in Formula 4.

[0207] In the present invention, the method for preparing the compound of the structure represented by Formula 10 preferably comprises the following steps:

[0208] (1) 2-chloro-4-fluoro-5-nitrobenzoic acid is dissolved in DMF, and then potassium carbonate is added and stirred at room temperature for 10 minutes. Different chloro(bromo)acetic acid ester derivatives are added. After the reaction is completed, the potassium carbonate is removed by filtration, and the mixture is extracted with ethyl acetate, concentrated, and purified by silica gel chromatography to obtain 2-chloro-4-fluoro-5-nitrobenzoic acid ester derivatives. The reaction equation is:

[0209]

[0210] (2) Dissolve 2-chloro-4-fluoro-5-nitrobenzoate derivatives in 90 vol% ethanol, then add ammonium chloride, stir and heat until reflux reaction, then slowly add iron powder and continue reflux reaction. After the reaction is completed, filter and collect the filtrate, concentrate and recrystallize to obtain compound 5-amino-2-chloro-4-fluorobenzoate derivatives; the reaction equation is:

[0211]

[0212] In the present invention, the compound containing the Het group is preferably

[0213] In the present invention, the compound of the N-phenyliminobenzoate derivative having the structure shown in Formula 4 is preferably a 2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorobenzoate derivative.

[0214] In the present invention, the preparation method of 2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorobenzoate derivatives preferably comprises the following steps: dissolving 5-amino-2-chloro-4-fluorobenzoate derivatives in glacial acetic acid, then adding 4,5,6,7-tetrahydroisobenzofuran-1,3-dione under stirring, and heating under reflux for reaction. After completion of the reaction, the target compound is extracted with ethyl acetate, dried, concentrated, and purified by silica gel chromatography. The reaction equation is:

[0215]

[0216] The present invention provides the use of the N-phenylimine derivatives described in the above technical solution or the N-phenylimine derivatives prepared by the preparation method described in the above technical solution as active components of herbicides.

[0217] In the present invention, the herbicides include post-emergence herbicides of grasses and / or post-emergence herbicides of broadleaf weeds.

[0218] Based on the N-phenylphthalimide structure, the present invention uses various substituted "imines" as pharmacophores to create N-phenylimine herbicides with relatively stable physical and chemical properties. At a dosage of 10 μg / mu, these herbicides exhibit a 28% to 50% post-emergence inhibition rate against barnyardgrass, a 34% to 56% post-emergence inhibition rate against crabgrass, a 50% to 70% post-emergence inhibition rate against foxtail grass, a 100% post-emergence inhibition rate against velvetleaf, a 100% post-emergence inhibition rate against purslane, and a 100% post-emergence inhibition rate against Amaranthus retroflexus. The control agent, fluazifop-butyl, exhibits a 40% to 90% post-emergence inhibition rate against gramineous plants and a 100% control effect against broadleaf weeds. While N-phenylimine compounds have a relatively poor control effect against gramineous weeds, they exhibit excellent control effect against broadleaf weeds. Among them, some compounds have a 100% control effect on velvetleaf, Amaranthus retroflexus, and Purslane at 2.5aig / mu.

[0219] The present invention has been experimentally confirmed to have a significant effect in inhibiting the growth of weeds, and has a simple structure, a simple preparation process, a low production cost, and a broad application prospect.

[0220] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0221] Example 1: A method for preparing 2-(5-((5-(5-bromo-2-methylphenyl)-1,2,4-oxadiazol-3-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (compound number A1), comprising the following steps:

[0222] (1) Preparation of (Z)-5-bromo-N'-hydroxy-2-methylbenzimidamine: The reaction equation is:

[0223]

[0224] 5-Bromo-2-methylbenzonitrile (5 g, 25.50 mM) and 50 mL of anhydrous ethanol were mixed in a 100 mL three-necked flask. NH2OH·HCl (5.47 g, 76.51 mM) was then added under ice-cooling. The pH of the system was then adjusted to neutral with 1 M NaOH. The ice-cooling bath was removed, and the temperature was raised to 90°C and refluxed for 4 h. After completion of the reaction, the product was evaporated under reduced pressure and cooled. A solid precipitated, which was then recrystallized from anhydrous ethanol to obtain a solid (5.02 g, 86%).

[0225] (2) Preparation of 3-(5-bromo-2-methylphenyl)-5-(chloromethyl)-1,2,4-oxadiazole: The reaction equation is:

[0226]

[0227] (Z)-5-Bromo-N'-hydroxy-2-methylbenzimidamine solid (5 g, 21.83 mM) was added to 30 mL of toluene as solvent under ice-cooling. Chloroacetyl chloride (4.93 g, 43.65 mM) and triethylamine (2.21 g, 21.83 mM) were then added. The mixture was then heated to 110°C and refluxed for reaction. After the reaction was complete, the mixture was directly extracted with ethyl acetate (60 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain a solid (4.96 g, 79%). 1 H NMR (500MHz, CDCl3) δ7.7 (d, J = 2.5 Hz, 1H), 7.4 (dd, J = 7.3, 2.6 Hz, 1H), 7.4–7.3 (m, 1H), 5.0 (s, 2H), 2.5 (d, J = 1.0 Hz, 3H).

[0228] (3) Preparation of 4-chloro-2-fluoro-5-aminophenol: The reaction equation is:

[0229]

[0230] 4-Chloro-2-fluoro-5-nitrophenol (10 g, 52.21 mM) was dissolved in 100 mL of 90% ethanol by volume in a 250 mL three-necked round-bottom flask. NH4Cl (8.75 g, 156.62 mM) was then added with stirring and the temperature was raised to 90°C for reaction. When the system was refluxed, Fe powder (8.38 g, 156.62 mM) was added in batches and refluxed for 3 h. After the reaction was complete, the mixture was filtered while hot and washed three times with hot ethanol. The filtrate was concentrated to yield a large amount of dark brown solid, which was recrystallized from ethanol to give 4-chloro-2-fluoro-5-aminophenol (7.76 g, 92%).

[0231] (4) Preparation of 2-(4-chloro-2-fluoro-5-hydroxybenzene)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione: The reaction equation is:

[0232]

[0233] 4-Chloro-2-fluoro-5-aminophenol (7g, 43.33mM) and 50mL of glacial acetic acid were mixed in a 100mL three-necked round-bottom flask, and then 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (7.25g, 47.66mM) was added. The system was heated to 100°C for reaction. After the reaction was completed, the system was poured into ice water. A large amount of milky white solid precipitated, which was filtered to obtain an off-white solid (11.40g, 89%). 1 H NMR (400MHz, DMSO-d6) δ 10.4 (s, 1H), 7.6 (d, J = 2.6 Hz, 1H), 7.3 (d, J = 2.6 Hz, 1H), 2.3 (d, J = 3.2 Hz, 4H), 1.7 (p, J = 2.9 Hz, 4H).

[0234] (5) Preparation of 2-(5-((3-(5-bromo-2-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione: The reaction equation is:

[0235]

[0236] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. Then, 3-(5-bromo-2-methylphenyl)-5-(chloromethyl)-1,2,4-oxadiazole (0.29 g, 1.01 mM) was added and the temperature was raised to 60°C and refluxed. After complete reaction, the potassium carbonate was removed by filtration, the mixture was extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.44 g, 88%).

[0237] Example 2: A method for preparing 2-(4-chloro-2-fluoro-5-((3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A2) comprising the following steps: The reaction equation is:

[0238]

[0239] Steps (1) to (4) are the same as in Example 1;

[0240] (5) Preparation of 2-(4-chloro-2-fluoro-5-((3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0241] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 3-(2-methylphenyl)-5-(chloromethyl)-1,2,4-oxadiazole (0.21 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After the reaction was complete, the mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.37 g, 80%).

[0242] Example 3: A method for preparing 2-(4-chloro-5-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A3), comprising the following steps: The reaction equation is:

[0243]

[0244] Steps (1) to (4) are the same as in Example 1

[0245] (5) Preparation of 2-(4-chloro-5-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0246] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(3-chlorophenyl)-1,2,4-oxadiazole (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.40 g, 81%).

[0247] Example 4: A method for preparing 2-(5-(3-(2-bromophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A4), comprising the following steps: The reaction equation is:

[0248]

[0249] Steps (1) to (4) are the same as in Example 1

[0250] (5) Preparation of 2-(5-(3-(2-bromophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0251] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 3-(2-bromophenyl)-5-(chloromethyl)-1,2,4-oxadiazole (0.28 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.44 g, 88%).

[0252] Example 5: A method for preparing 2-(4-chloro-5-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A5), comprising the following steps: The reaction equation is:

[0253]

[0254] Steps (1) to (4) are the same as in Example 1

[0255] (5) Preparation of 2-(4-chloro-5-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0256] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.40 g, 80%).

[0257] Example 6: A method for preparing 2-(4-chloro-5-(3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A6), comprising the following steps: The reaction equation is:

[0258]

[0259] Steps (1) to (4) are the same as in Example 1

[0260] (5) Preparation of 2-(4-chloro-5-(3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0261] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(2,4-difluorophenyl)-1,2,4-oxadiazole (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.38 g, 76%).

[0262] Example 7: A method for preparing 2-(4-chloro-5-(3-(4-chloro-2-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A7), comprising the following steps: The reaction equation is:

[0263]

[0264] Steps (1) to (4) are the same as in Example 1

[0265] (5) Preparation of 2-(4-chloro-5-(3-(4-chloro-2-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0266] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. Then, 3-(4-chloro-2-fluorophenyl)-5-(chloromethyl)-1,2,4-oxadiazole (0.25 g, 1.01 mM) was added and the temperature was raised to 60°C and refluxed. After complete reaction, the potassium carbonate was removed by filtration, the mixture was extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.42 g, 88%).

[0267] Example 8: A method for preparing 2-(4-chloro-5-(3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A8), comprising the following steps: The reaction equation is:

[0268]

[0269] Steps (1) to (4) are the same as in Example 1

[0270] (5) Preparation of 2-(4-chloro-5-(3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0271] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(2-chlorophenyl)-1,2,4-oxadiazole (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.37 g, 75%).

[0272] Example 9: A method for preparing 2-(4-chloro-2-fluoro-5-(3-(2-fluoro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A9), comprising the following steps: The reaction equation is:

[0273]

[0274] Steps (1) to (4) are the same as in Example 1

[0275] (5) Preparation of 2-(4-chloro-2-fluoro-5-(3-(2-fluoro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0276] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(2-fluoro-4-methylphenyl)-1,2,4-oxadiazole (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.38 g, 78%).

[0277] Example 10: A method for preparing 2-(4-chloro-5-(3-(4-chloro-6-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A10), comprising the following steps: The reaction equation is:

[0278]

[0279] Steps (1) to (4) are the same as in Example 1

[0280] (5) Preparation of 2-(4-chloro-5-(3-(4-chloro-6-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0281] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. Then, 3-(2-chloro-4-(trifluoromethyl)pyridinyl)-5-(chloromethyl)-1,2,4-oxadiazole (0.30 g, 1.01 mM) was added and the temperature was raised to 60°C and refluxed. After complete reaction, the potassium carbonate was removed by filtration, the mixture was extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.45 g, 80%).

[0282] Example 11: A method for preparing 2-(4-chloro-5-(3-(2,4-dibromophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A11), comprising the following steps: The reaction equation is:

[0283]

[0284] Steps (1) to (4) are the same as in Example 1

[0285] (5) Preparation of 2-(4-chloro-5-(3-(2,4-dibromophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione

[0286] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(2,4-dibromophenyl)-1,2,4-oxadiazole (0.36 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.42 g, 84%).

[0287] Example 12: A method for preparing 2-(4-chloro-2-fluoro-5-(3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A12), comprising the following steps: The reaction equation is:

[0288]

[0289] Steps (1) to (4) are the same as in Example 1

[0290] (5) Preparation of 2-(4-chloro-2-fluoro-5-(3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0291] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(2-fluorophenyl)-1,2,4-oxadiazole (0.20 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After the reaction was complete, the mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.41 g, 84%).

[0292] Example 13: A method for preparing 2-(3-(3-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A13), comprising the following steps: The reaction equation is:

[0293]

[0294] Steps (1) to (4) are the same as in Example 1

[0295] (5) Preparation of 2-(3-(3-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0296] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 3-(3-bromo-5-fluorophenyl)-5-(chloromethyl)-1,2,4-oxadiazole (0.30 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.44 g, 88%).

[0297] Example 14: A method for preparing 2-(4-chloro-5-(3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A14), comprising the following steps: The reaction equation is:

[0298]

[0299] Steps (1) to (4) are the same as in Example 1

[0300] (5) Preparation of 2-(4-chloro-5-(3-(3,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0301] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(3,4-difluorophenyl)-1,2,4-oxadiazole (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.38 g, 78%).

[0302] Example 15: A method for preparing 2-(4-chloro-5-(3-(2-chloro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A15), comprising the following steps: The reaction equation is:

[0303]

[0304] Steps (1) to (4) are the same as in Example 1

[0305] (5) Preparation of 2-(4-chloro-5-(3-(2-chloro-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0306] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(2-chloro-4-methylphenyl)-1,2,4-oxadiazole (0.25 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.44 g, 84%).

[0307] Example 16: A method for preparing 2-(4-chloro-5-(3-(2,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A16), comprising the following steps: The reaction equation is:

[0308]

[0309] Steps (1) to (4) are the same as in Example 1

[0310] (5) Preparation of 2-(4-chloro-5-(3-(2,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0311] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(2,6-dichloropyridin-3-yl)-1,2,4-oxadiazole (0.27 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.47 g, 90%).

[0312] Example 17: A method for preparing 2-(4-chloro-2-fluoro-5-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A17), comprising the following steps: The reaction equation is:

[0313]

[0314] Steps (1) to (4) are the same as in Example 1

[0315] (5) Preparation of 2-(4-chloro-2-fluoro-5-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0316] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (0.27 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.44 g, 89%).

[0317] Example 18: A method for preparing 2-(4-chloro-2-fluoro-5-(3-(2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A18), comprising the following steps: The reaction equation is:

[0318]

[0319] Steps (1) to (4) are the same as in Example 1

[0320] (5) Preparation of 2-(4-chloro-2-fluoro-5-(3-(2-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0321] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(2-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (0.27 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.46 g, 88%).

[0322] Example 19: A method for preparing 2-(4-chloro-2-fluoro-5-(3-(thiophen-2-yl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A19), comprising the following steps: The reaction equation is:

[0323]

[0324] Steps (1) to (4) are the same as in Example 1

[0325] (5) Preparation of 2-(4-chloro-2-fluoro-5-(3-(thiophen-2-yl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0326] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(thien-2-yl)-1,2,4-oxadiazole (0.2 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.33 g, 85%).

[0327] Example 20: A method for preparing 2-(4-chloro-2-fluoro-5-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A20), comprising the following steps: The reaction equation is:

[0328]

[0329] Steps (1) to (4) are the same as in Example 1

[0330] (5) Preparation of 2-(4-chloro-2-fluoro-5-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0331] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (0.28 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.46 g, 88%).

[0332] Example 21: A method for preparing 2-(4-chloro-5-(3-(2-chloro-5-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A21), comprising the following steps: The reaction equation is:

[0333]

[0334] Steps (1) to (4) are the same as in Example 1

[0335] (5) Preparation of 2-(4-chloro-5-(3-(2-chloro-5-fluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0336] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. Then, 3-(2-chloro-5-fluorophenyl)-5-(chloromethyl)-1,2,4-oxadiazole (0.25 g, 1.01 mM) was added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.39 g, 78%).

[0337] Example 22: A method for preparing 2-(4-chloro-2-fluoro-5-(3-(furan-2-yl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A22), comprising the following steps: The reaction equation is:

[0338]

[0339] Steps (1) to (4) are the same as in Example 1

[0340] (5) Preparation of 2-(4-chloro-2-fluoro-5-(3-(furan-2-yl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0341] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(furan-2-yl)-1,2,4-oxadiazole (0.19 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.43 g, 88%).

[0342] Example 23: A method for preparing 2-(4-chloro-2-fluoro-5-(3-(4-fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A23), comprising the following steps: The reaction equation is:

[0343]

[0344] Steps (1) to (4) are the same as in Example 1

[0345] (5) Preparation of 2-(4-chloro-2-fluoro-5-(3-(4-fluoro-2-methylphenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0346] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(4-fluoro-2-methylphenyl)-1,2,4-oxadiazole (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.39 g, 79%).

[0347] Example 24: A method for preparing 2-(4-chloro-5-(3-(2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A24), comprising the following steps: The reaction equation is:

[0348]

[0349] Steps (1) to (4) are the same as in Example 1

[0350] (5) Preparation of 2-(4-chloro-5-(3-(2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0351] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(2,6-difluorophenyl)-1,2,4-oxadiazole (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After the reaction was complete, the mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.41 g, 83%).

[0352] Example 25: A method for preparing 2-(4-chloro-2-fluoro-5-(3-phenyl-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A25), comprising the following steps: The reaction equation is:

[0353]

[0354] Steps (1) to (4) are the same as in Example 1

[0355] (5) Preparation of 2-(4-chloro-2-fluoro-5-(3-phenyl-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0356] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole (0.20 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.40 g, 81%).

[0357] Example 26: A method for preparing 2-(5-(3-(4-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A26), comprising the following steps: The reaction equation is:

[0358]

[0359] Steps (1) to (4) are the same as in Example 1

[0360] (5) Preparation of 2-(5-(3-(4-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0361] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 3-(4-(tert-butyl)phenyl)-5-(chloromethyl)-1,2,4-oxadiazole (0.25 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.43 g, 87%).

[0362] Example 27: A method for preparing 2-(4-chloro-2-fluoro-5-(3-(4-iodophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (A27), comprising the following steps: The reaction equation is:

[0363]

[0364] Steps (1) to (4) are the same as in Example 1

[0365] (5) Preparation of 2-(4-chloro-2-fluoro-5-(3-(4-iodophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0366] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 5-(chloromethyl)-3-(4-iodophenyl)-1,2,4-oxadiazole (0.33 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.42 g, 85%).

[0367] Example 28: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (compound number B1), comprising the following steps:

[0368] (1) Preparation of 2-fluorobenzoylhydrazine: The reaction equation is:

[0369]

[0370] 2-Fluorobenzoic acid (5 g, 35.69 mM) was mixed with 30 mL of anhydrous ethanol in a 100 mL three-necked flask. Concentrated sulfuric acid (10 g, 107.06 mM) was then slowly added dropwise under an ice bath. After stirring for 1 h, the mixture was heated to 90°C and refluxed. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature and slowly poured into water. The pH was adjusted to neutral with sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain an oily liquid. The solid (6.00 g, 86%) was purified on a silica gel column using petroleum ether:ethyl acetate (v / v=4:1) as the eluent. Ethyl 2-fluorobenzoate (5 g, 29.73 mM) was added with 30 mL of anhydrous ethanol at room temperature. 80% hydrazine hydrate (1.49 g, 29.73 mM) was added and the mixture was heated to 80°C and refluxed for 3 h. After the reaction was completed, the solvent was distilled off under reduced pressure and the residue was recrystallized from ethanol to obtain a solid (5.00 g, 79%).

[0371] (2) Preparation of 2-(chloromethyl)-5-(3-fluorophenyl)-1,3,4-oxadiazole: The reaction equation is:

[0372]

[0373] Dissolve 3-fluorobenzoyl hydrazine (0.73 g, 3.67 mM) in 15 mL of 1,2-dichloroethane and stir for a while. Add chloroacetic acid (0.70 g, 7.33 mM) and phosphorus oxychloride (1.70 g, 11.0 mM). Heat to 90°C and reflux for reaction. Monitor the reaction by TLC. After the reaction is complete, quench with ice water, adjust the pH to neutral with saturated sodium bicarbonate, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and purify by silica gel chromatography to obtain a white solid (0.63 g, 70%). 1 H NMR (400MHz, CDCl3) δ7.9 (ddd, J=7.8, 1.6, 1.0Hz, 1H), 7.8 (ddd, J=9.0, 2.6, 1.5 Hz, 1H), 7.5 (td, J=8.1, 5.5Hz, 1H), 7.3 (tdd, J=8.3, 2.6, 1.0Hz, 1H), 4.8 (s, 2H).

[0374] (3) Preparation of 4-chloro-2-fluoro-5-aminophenol: The reaction equation is:

[0375]

[0376] 4-Chloro-2-fluoro-5-nitrophenol (10 g, 52.21 mM) was dissolved in 100 mL of 90% ethanol by volume in a 250 mL three-necked round-bottom flask. NH4Cl (8.75 g, 156.62 mM) was then added with stirring and the temperature was raised to 90°C for reaction. When the system was refluxed, Fe powder (8.38 g, 156.62 mM) was added in batches and refluxed for 3 h. After the reaction was complete, the mixture was filtered while hot and washed three times with hot ethanol. The filtrate was concentrated to yield a large amount of dark brown solid, which was recrystallized from ethanol to give 4-chloro-2-fluoro-5-aminophenol (7.76 g, 92%).

[0377] (4) Preparation of 2-(4-chloro-2-fluoro-5-hydroxybenzene)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione: The reaction equation is:

[0378]

[0379] 4-Chloro-2-fluoro-5-aminophenol (7 g, 43.33 mM) and 50 mL of glacial acetic acid were mixed in a 100 mL three-necked round-bottom flask. 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (7.25 g, 47.66 mM) was then added. The system was heated to 100°C for reaction. After the reaction, the system was poured into ice water, whereupon a large amount of milky white solid precipitated. Filtration afforded an off-white solid (11.40 g, 89%).

[0380] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(3-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione: The reaction equation is:

[0381]

[0382] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione was added.

[0383] 2-(4-Chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 2-(Chloromethyl)-5-(3-fluorophenyl)-1,3,4-oxadiazole (0.24 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.41 g, 88%).

[0384] Example 29: A method for preparing 2-(4-chloro-5-((5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B2), comprising the following steps: The reaction equation is:

[0385]

[0386] Steps (1) to (4) are the same as in Example 28

[0387] (5) Preparation of 2-(4-chloro-5-((5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0388] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(3-chlorophenyl)-1,3,4-oxadiazole (0.26 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.43 g, 81%).

[0389] Example 30: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(3-methylphenyl)-1,3,4-oxadiazole-2-methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B3), comprising the following steps: The reaction equation is:

[0390]

[0391] Steps (1) to (4) are the same as in Example 28

[0392] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(3-methylphenyl)-1,3,4-oxadiazole-2-methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0393] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(3-methylphenyl)-1,3,4-oxadiazole (0.24 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.35 g, 75%).

[0394] Example 31: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B4), comprising the following steps: The reaction equation is:

[0395]

[0396] Steps (1) to (4) are the same as in Example 28

[0397] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0398] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(Chloromethyl)-5-(2-fluorophenyl)-1,3,4-oxadiazole (0.24 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.37 g, 78%).

[0399] Example 32: A method for preparing 2-(4-chloro-5-(5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B5), comprising the following steps: The reaction equation is:

[0400]

[0401] Steps (1) to (4) are the same as in Example 28

[0402] (5) Preparation of 2-(4-chloro-5-(5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0403] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(2-chlorophenyl)-1,3,4-oxadiazole (0.26 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.36 g, 79%).

[0404] Example 33: A method for preparing 2-(5-(5-(2-bromophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B6), comprising the following steps: The reaction equation is:

[0405]

[0406] Steps (1) to (4) are the same as in Example 28

[0407] (5) Preparation of 2-(5-(5-(2-bromophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0408] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(2-bromophenyl)-1,3,4-oxadiazole (0.31 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.31 g, 75%).

[0409] Example 34: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(2-iodophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B7), comprising the following steps: The reaction equation is:

[0410]

[0411] Steps (1) to (4) are the same as in Example 28

[0412] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(2-iodophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0413] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(2-iodophenyl)-1,3,4-oxadiazole (0.37 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.33 g, 77%).

[0414] Example 35: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B8), comprising the following steps: The reaction equation is:

[0415]

[0416] Steps (1) to (4) are the same as in Example 28

[0417] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0418] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(2-nitrophenyl)-1,3,4-oxadiazole (0.28 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.30 g, 65%).

[0419] Example 36: A method for preparing 2-(4-chloro-2-fluoro-5-((5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B9), comprising the following steps: The reaction equation is:

[0420]

[0421] Steps (1) to (4) are the same as in Example 28

[0422] (5) Preparation of 2-(4-chloro-2-fluoro-5-((5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0423] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(2-methylphenyl)-1,3,4-oxadiazole (0.24 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.37 g, 78%).

[0424] Example 37: A method for preparing 2-(5-(5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B10), comprising the following steps: The reaction equation is:

[0425]

[0426] Steps (1) to (4) are the same as in Example 28

[0427] (5) Preparation of 2-(5-(5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0428] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(3-bromophenyl)-5-(chloromethyl)-1,3,4-oxadiazole (0.31 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.39 g, 79%).

[0429] Example 38: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(3-iodophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B11), comprising the following steps: The reaction equation is:

[0430]

[0431] Steps (1) to (4) are the same as in Example 28

[0432] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(3-iodophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0433] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(3-iodophenyl)-1,3,4-oxadiazole (0.37 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.34 g, 76%).

[0434] Example 39: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B12) comprising the following steps: The reaction equation is:

[0435]

[0436] Steps (1) to (4) are the same as in Example 28

[0437] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0438] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(3-nitromethyl)-1,3,4-oxadiazole (0.28 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.36 g, 74%).

[0439] Example 40: A method for preparing 2-(4-chloro-2-fluoro-5-((5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B13), comprising the following steps: The reaction equation is:

[0440]

[0441] Steps (1) to (4) are the same as in Example 28

[0442] (5) Preparation of 2-(4-chloro-2-fluoro-5-((5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0443] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(4-methylphenyl)-1,3,4-oxadiazole (0.24 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.36 g, 81%).

[0444] Example 41: The preparation method of 2-(4-chloro-2-fluoro-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B14) comprises the following steps: The reaction equation is:

[0445]

[0446] Steps (1) to (4) are the same as in Example 28

[0447] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0448] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(4-fluorophenyl)-1,3,4-oxadiazole (0.24 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.32 g, 76%).

[0449] Example 42: A method for preparing 2-(4-chloro-5-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B15), comprising the following steps: The reaction equation is:

[0450]

[0451] Steps (1) to (4) are the same as in Example 28

[0452] (5) Preparation of 2-(4-chloro-5-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0453] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole (0.26 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.35 g, 75%).

[0454] Example 43: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B16), comprising the following steps: The reaction equation is:

[0455]

[0456] Steps (1) to (4) are the same as in Example 28

[0457] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0458] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(4-bromophenyl)-1,3,4-oxadiazole (0.31 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.33 g, 71%).

[0459] Example 44: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B17), comprising the following steps: The reaction equation is:

[0460]

[0461] Steps (1) to (4) are the same as in Example 28

[0462] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0463] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(4-iodophenyl)-1,3,4-oxadiazole (0.37 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.36 g, 79%).

[0464] Example 45: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B18), comprising the following steps: The reaction equation is:

[0465]

[0466] Steps (1) to (4) are the same as in Example 28

[0467] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0468] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(4-nitrophenyl)-1,3,4-oxadiazole (0.28 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.35 g, 78%).

[0469] Example 46: A method for preparing 2-(4-chloro-5-(5-(4-chloro-2-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B19), comprising the following steps: The reaction equation is:

[0470]

[0471] Steps (1) to (4) are the same as in Example 28

[0472] (5) Preparation of 2-(4-chloro-5-(5-(4-chloro-2-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0473] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(4-chloro-2-fluorophenyl)-5-(chloromethyl)-1,3,4-oxadiazole (0.28 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.31 g, 65%).

[0474] Example 47: A method for preparing 2-(4-chloro-2-fluoro-5-(5-(2-fluoro-4-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (B20) comprising the following steps: The reaction equation is:

[0475]

[0476] Steps (1) to (4) are the same as in Example 28

[0477] (5) Preparation of 2-(4-chloro-2-fluoro-5-(5-(2-fluoro-4-nitrophenyl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0478] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.17 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.49 g, 3.52 mM) was added and stirred for 30 minutes. 2-(chloromethyl)-5-(2-fluoro-4-nitrophenyl)-1,3,4-oxadiazole (0.30 g, 1.17 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.33 g, 75%).

[0479] Example 48: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C1), comprising the following steps:

[0480] (1) Preparation of α-bromo(chloro)acetophenone: The reaction equation is:

[0481]

[0482] Add acetophenone (12g, 100mM) and 50mL of water as solvent to a three-necked flask, slowly stir and heat to 90°C, then slowly add liquid bromine (16.8g, 105mM), maintain the temperature at 60°C, and continue stirring for 4h, then cool to room temperature, filter, and recrystallize from methanol to obtain the product. 1 H NMR (500MHz, CDCl3) δ8.0–7.9(m,2H),7.6–7.5(m,3H),4.7(s,2H).

[0483] (2) Preparation of 2-(4-chloro-2-fluoro-5-hydroxybenzene)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione:

[0484] The steps are the same as in Example 1

[0485] (3) Preparation of 2-(4-chloro-2-fluoro-5-(2-oxo-2-phenylethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione: The reaction equation is:

[0486]

[0487] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 2-bromoacetophenone (0.20 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.38 g, 81%).

[0488] Example 49: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-methyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C2) comprising the following steps: The reaction equation is:

[0489]

[0490] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 2-Bromo-1-(4-methylphenyl)ethanone (0.22 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the potassium carbonate was removed by filtration, the mixture was extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.35 g, 83%).

[0491] Example 50: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-cyanophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C3) comprising the following steps: The reaction equation is:

[0492]

[0493] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.04 mM) was added and stirred for 30 minutes. 2-Bromo-1-(4-cyanophenyl)ethanone (0.24 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.34 g, 75%).

[0494] Example 51: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(2-fluorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C4), comprising the following steps: The reaction equation is:

[0495]

[0496] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(2-fluorophenyl)ethanone (0.20 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.35 g, 78%).

[0497] Example 52: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(3,5-difluorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C5) comprising the following steps: The reaction equation is:

[0498]

[0499] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(3,5-difluorophenyl)ethanone (0.24 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.32 g, 74%).

[0500] Example 53: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(2-methoxyphenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C6) comprising the following steps: The reaction equation is:

[0501]

[0502] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(2-methoxyphenyl)ethanone (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.33 g, 70%).

[0503] Example 54: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(3-fluorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C7) comprising the following steps: The reaction equation is:

[0504]

[0505] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(3-fluorophenyl)ethanone (0.22 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After the reaction was complete, the potassium carbonate was removed by filtration, the mixture was extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.32 g, 79%).

[0506] Example 55: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-fluorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C8) comprising the following steps: The reaction equation is:

[0507]

[0508] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(4-fluorophenyl)ethanone (0.22 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.36 g, 82%).

[0509] Example 56: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-nitrophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C9) comprising the following steps: The reaction equation is:

[0510]

[0511] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(4-nitrobenzene)ethanone (0.25 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After the reaction was complete, the potassium carbonate was removed by filtration, the mixture was extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.34 g, 75%).

[0512] Example 57: A method for preparing 2-(4-chloro-2-fluoro-5-((4-fluorobenzyl)oxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C10), comprising the following steps: The reaction equation is:

[0513]

[0514] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 1-(chloromethyl)-4-fluorobenzene (0.15 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the potassium carbonate was removed by filtration, the mixture was extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.35 g, 75%).

[0515] Example 58: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-chlorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C11) comprising the following steps: The reaction equation is:

[0516]

[0517] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(4-chlorophenyl)ethanone (0.24 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.31 g, 68%).

[0518] Example 59: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(2,4-difluorophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C12) comprising the following steps: The reaction equation is:

[0519]

[0520] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(2,4-difluorophenyl)ethanone (0.24 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.32 g, 69%).

[0521] Example 60: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-methoxyphenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C13) comprising the following steps: The reaction equation is:

[0522]

[0523] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(4-methoxyphenyl)ethanone (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the potassium carbonate was removed by filtration, the mixture was extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.35 g, 75%).

[0524] Example 61: A method for preparing 2-(4-chloro-2-fluoro-5-(2-oxo-2-(4-bromophenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C14), comprising the following steps: The reaction equation is:

[0525]

[0526] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(4-bromophenyl)ethanone (0.23 g, 1.01 mM) was then added and the temperature was raised to 60°C and refluxed. After complete reaction, the reaction mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.34 g, 73%).

[0527] Example 62: A method for preparing 2-(2-fluoro-4-(2-oxo-2-(4-methylphenyl)ethoxy)phenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (C15) comprising the following steps: The reaction equation is:

[0528]

[0529] At room temperature, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.30 g, 1.01 mM) was dissolved in 15 mL of acetone in a 25 mL three-necked flask. Potassium carbonate (0.42 g, 3.01 mM) was added and stirred for 30 minutes. 2-Bromo-1-(4-methylphenyl)ethanone (0.22 g, 1.01 mM) was then added and the mixture was heated to 60°C and refluxed. After complete reaction, the mixture was filtered to remove the potassium carbonate, extracted, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to obtain the title compound (0.32 g, 73%).

[0530] Example 63: A method for preparing N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)acetamide (D1), comprising the following steps:

[0531] (1) Preparation of 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione: The reaction equation is:

[0532]

[0533] Dissolve 4-chloro-2-fluoroaniline (10.0 g, 68.7 mM) in glacial acetic acid, then add 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (10.45 g, 68.7 mM) under stirring and heat under reflux for reaction. After the reaction is completed, pour the system into ice water and stir continuously. A large amount of solid precipitates, which is filtered and the filter cake is washed three times with saturated sodium bicarbonate solution and dried for later use.1 H NMR (400MHz, CDCl3) δ7.6 (dd, J=7.9, 5.1Hz, 1H), 7.3 (ddd, J=8.2, 4.3, 2.0Hz, 2H), 2.4 (m, J=3.1Hz, 4H), 1.9–1.6 (m, 4H).

[0534] (2) Preparation of 2-(4-chloro-2-fluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione: The reaction equation is:

[0535]

[0536] Dissolve 2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (15g, 53.63mM) in 80% sulfuric acid (50mL) and slowly add concentrated nitric acid (7.0g, 107.3mM) dropwise at -15°C, maintaining the temperature until the reaction is complete. After the reaction is complete, pour the system into ice water and stir continuously. A large amount of yellow solid precipitates. Filter and wash the filter cake three times with saturated sodium bicarbonate solution and dry for later use. 1 H NMR (400MHz, CDCl3) δ8.5 (d, J = 5.0Hz, 1H), 7.7 (d, J = 8.0Hz, 1H), 2.4 (p, J = 3.4Hz, 4H), 1.8 (p, J = 3.3Hz, 4H).

[0537] (3) Preparation of 2-(5-amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione: The reaction equation is:

[0538]

[0539] 2-(4-chloro-2-fluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (15.0g, 46.20mM) was dissolved in 90% ethanol by volume, and then ammonium chloride (12.9g, 230.99mM) was added, stirred and heated to reflux reaction, and then iron powder (12.36g, 230.99mM) was slowly added, and the reflux reaction was continued. After the reaction was completed, the filtrate was filtered, concentrated, and recrystallized to obtain the compound 2-(5-amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione. Its compound 1H NMR (400MHz, CDCl3) δ7.5 (d, J = 8.0 Hz, 1H), 7.2 (d, J = 4.9 Hz, 1H), 4.8 (s, 2H), 2.4 (m, J = 2.9 Hz, 4H), 1.9–1.3 (m, 4H).

[0540] (4) Preparation of N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)acetamide: The reaction equation is:

[0541]

[0542] 2-(5-Amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.5 g, 1.70 mM) was added to dichloromethane as a solvent. Acetyl chloride (0.15 g, 1.87 mM) and triethylamine (0.18 g, 1.70 mM) were added as catalysts under ice-cooling. The mixture was stirred at room temperature. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the title compound (0.48 g, 80%).

[0543] Example 64: A method for preparing 2-chloro-N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)acetamide (D2) comprising the following steps: The reaction equation is:

[0544]

[0545] 2-(5-Amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.5 g, 1.70 mM) was dissolved in dichloromethane. Chloroyl chloride (0.21 g, 1.87 mM) and triethylamine (0.17 g, 1.70 mM) were added under ice-cooling. After stirring for 10 minutes, the ice-cooling bath was removed and the reaction was allowed to stir at room temperature. After completion of the reaction, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the title compound (0.35 g, 74%).

[0546] Example 65: A method for preparing 2-bromo-N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)propanamide (D3) comprising the following steps: The reaction equation is:

[0547]

[0548] 2-(5-Amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.5 g, 1.70 mM) was dissolved in dichloromethane. 2-Bromopropionyl chloride (0.32 g, 1.87 mM) and triethylamine (0.08 g, 0.85 mM) were added under ice-cooling. After stirring for 10 minutes, the ice-cooling bath was removed and the reaction was allowed to stir at room temperature. After completion of the reaction, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the title compound (0.33 g, 72%).

[0549] Example 66: A method for preparing 3-chloro-N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)-2,2-dimethylpropionamide (D4) comprising the following steps: The reaction equation is:

[0550]

[0551] 2-(5-Amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.5 g, 1.70 mM) was dissolved in dichloromethane. 3-Chloro-2,2-dimethylpropanoyl chloride (0.29 g, 1.87 mM) and triethylamine (0.08 g, 0.85 mM) were added under ice-cooling. After stirring for 10 minutes, the ice-cooling bath was removed and the reaction was allowed to stir at room temperature. After completion of the reaction, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the title compound (0.34 g, 70%).

[0552] Example 67: A method for preparing (E)-N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)but-2-enamide (D5), comprising the following steps: The reaction equation is:

[0553]

[0554] 2-(5-Amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.5 g, 1.70 mM) was dissolved in dichloromethane. (E)-But-2-enoyl chloride (0.20 g, 1.87 mM) and triethylamine (0.08 g, 0.85 mM) were added under ice-cooling. After stirring for 10 minutes, the ice-cooling bath was removed and the reaction was allowed to stir at room temperature. After completion of the reaction, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the title compound (0.31 g, 80%).

[0555] Example 68: A method for preparing ethyl 3-((2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)amino)-3-oxopropanoate (D6), comprising the following steps: The reaction equation is:

[0556]

[0557] 2-(5-Amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.5 g, 1.70 mM) was dissolved in dichloromethane. Ethyl 3-chloro-3-oxopropanoate (0.28 g, 1.87 mM) and triethylamine (0.08 g, 0.85 mM) were added under ice-cooling. After stirring for 10 minutes, the ice-cooling bath was removed and the reaction was allowed to stir at room temperature. After completion of the reaction, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the title compound (0.31 g, 76%).

[0558] Example 69: A method for preparing N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)nonanamide (D7), comprising the following steps: The reaction equation is:

[0559]

[0560] 2-(5-Amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.5 g, 1.70 mM) was dissolved in dichloromethane. Nonanoyl chloride (0.33 g, 1.87 mM) and triethylamine (0.08 g, 0.85 mM) were added under ice-cooling. After stirring for 10 minutes, the ice-cooling bath was removed and the reaction was allowed to stir at room temperature. After completion of the reaction, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the title compound (0.32 g, 74%).

[0561] Example 70: A method for preparing N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)cyclopropanecarboxamide (D8), comprising the following steps: The reaction equation is:

[0562]

[0563] 2-(5-Amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.5 g, 1.70 mM) was dissolved in dichloromethane. Cyclopropanoyl chloride (0.20 g, 1.87 mM) and triethylamine (0.08 g, 0.85 mM) were added under ice-cooling. After stirring for 10 minutes, the ice-cooling bath was removed and the reaction was allowed to stir at room temperature. After completion of the reaction, the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the title compound (0.31 g, 71%).

[0564] Example 71: A method for preparing N-(2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)cyclobutanecarboxamide (D9), comprising the following steps: The reaction equation is:

[0565]

[0566] 2-(5-Amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.5 g, 1.70 mM) was dissolved in dichloromethane. Cyclobutanoyl chloride (0.22 g, 1.87 mM) and triethylamine (0.08 g, 0.85 mM) were added under ice-cooling. After stirring for 10 minutes, the ice-cooling bath was removed and the reaction was allowed to stir at room temperature. After completion of the reaction, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the title compound (0.32 g, 73%).

[0567] Example 72: A method for preparing N-(2-chloro-5-(1,3-dioxy-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorophenyl)cyclohexanecarboxamide (D10) comprising the following steps: The reaction equation is:

[0568]

[0569] 2-(5-Amino-4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione (0.5 g, 1.70 mM) was dissolved in dichloromethane. Cyclohexanoyl chloride (0.27 g, 1.87 mM) and triethylamine (0.08 g, 0.85 mM) were added under ice-cooling. After stirring for 10 minutes, the ice-cooling bath was removed and the reaction was allowed to stir at room temperature. After completion of the reaction, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the title compound (0.32 g, 75%).

[0570] Example 73: A method for preparing 2-(4-chlorophenyl)-2-oxoethyl-2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorobenzoate (E1), comprising the following steps:

[0571] (1) Preparation of 2-(4-chlorophenyl)-2-oxoethyl-2-chloro-4-fluoro-5-nitrobenzoate: The reaction equation is:

[0572]

[0573] 2-Chloro-4-fluoro-5-nitrobenzoic acid (1.0 g, 4.55 mM) was dissolved in 15 mL of DMF, and then potassium carbonate (1.89 g, 13.66 mM) was added. After stirring at room temperature for 10 minutes, 2-bromo-1-(4-chlorophenyl)ethan-1-one (1.06 g, 4.55 mM) was added. After the reaction was complete, potassium carbonate was removed by filtration, and the mixture was extracted with ethyl acetate, concentrated, and purified by silica gel chromatography to obtain a white solid (1.26 g, 80%). 1 H NMR (400MHz, CDCl3) δ8.5 (d, J = 4.9 Hz, 1H), 8.1 (dd, J = 8.6, 5.0 Hz, 2H), 7.7 (d, J = 7.9 Hz, 1H), 7.3 (t, J = 8.3 Hz, 2H), 5.7 (s, 2H).

[0574] (2) Preparation of 2-(4-chlorophenyl)-2-oxoethyl-5-amino-2-chloro-4-fluorobenzoate: The reaction equation is:

[0575]

[0576] 2-(4-chlorophenyl)-2-oxoethyl-2-chloro-4-fluoro-5-nitrobenzoate (1.0 g, 2.69 mM) was dissolved in 15 mL of 90% ethanol, and then ammonium chloride (0.75 g, 13.44 mM) was added. The mixture was stirred and heated to reflux, and then iron powder (0.72 g, 13.44 mM) was slowly added. The reflux reaction was continued. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and the compound was recrystallized. 1 H NMR (400MHz, CDCl3) δ8.1 (dd, J=8.6, 5.0Hz, 2H), 7.5 (d, J=7.9Hz, 1H), 7.4 (d, J=4.9Hz, 1H), 7.3 (t, J=8.3Hz, 2H), 5.7 (s, 2H), 4.5 (s, 2H).

[0577] (3) Preparation of 2-(4-chlorophenyl)-2-oxoethyl-2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorobenzoate: The reaction equation is:

[0578]

[0579] Dissolve 2-(4-chlorophenyl)-2-oxoethyl-5-amino-2-chloro-4-fluorobenzoate (0.50 g, 1.46 mM) in 15 mL of glacial acetic acid, then add 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (0.22 g, 1.46 mM) with stirring. Heat under reflux to react. After completion of the reaction, extract with ethyl acetate, dry, concentrate, and purify the title compound (0.56 g, 81%) by silica gel chromatography.

[0580] Example 74: A method for preparing 2-oxo-2-phenethyl-2-chloro-5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-4-fluorobenzoate (E2), comprising the following steps: The reaction equation is:

[0581]

[0582] Dissolve 2-phenyl-2-oxoethyl-5-amino-2-chloro-4-fluorobenzoate (0.50 g, 1.62 mM) in 15 mL of glacial acetic acid, then add 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (0.25 g, 1.62 mM) with stirring. Heat under reflux to react. After completion of the reaction, extract with ethyl acetate, dry, concentrate, and purify the title compound (0.54 g, 78%) by silica gel chromatography.

[0583] The physicochemical properties and spectral data of the target compounds prepared in the above examples are shown in Table 1:

[0584] Table 1 Physicochemical properties and spectral data of the target compounds prepared in Examples 1-74

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596] Example Post-emergence herbicidal activity test of target compound:

[0597] (1) Post-seedling stem and leaf spray treatment:

[0598] Weeds were cultivated using the potting method, using 180×140 mm plastic pots placed in enamel trays filled with air-dried, sieved topsoil collected from the field (4 / 5 locations). Initial soil moisture was maintained at 20%. Weed seeds with plump, uniform seeds were selected and soaked in 25°C warm water for 6 hours. Germination was accelerated in a 28°C biochemical incubator (dark). Just-white weed seeds were evenly distributed on the soil surface and covered with 0.5–1 cm of soil, depending on seed size. Cultivation was carried out in a controlled sunlight greenhouse at 20–30°C, natural light, and a relative humidity of 57–72%. The soil was loam with an organic matter content of 1.63%, a pH of 7, 84.3 mg / kg of alkaline-hydrolyzable nitrogen, 38.5 mg / kg of available phosphorus, and 82.1 mg / kg of available potassium.

[0599] Each treatment was replicated twice, with 12 pots treated each time. Twenty weed seeds were sown per pot. The drug was applied once. When weeds reached the 1.5- to 2-leaf stage, thinning was performed to maintain a minimum of 10 weeds per pot, resulting in a total of 30 weeds per treatment.

[0600] Place the cultivated weeds in an area of ​​0.1m 2 Place the weeds on a tray and spray the stems and leaves with a sprayer. After the spraying is completed, move the sprayed weeds into the greenhouse for conventional cultivation.

[0601] Two weeks after sowing, when the test plants were at the 2-3 leaf stage, the test compounds of the invention were dissolved in acetone, Tween 80 was added, and 1.5 L / ha of methyl oleate emulsifiable concentrate was diluted with water to a desired concentration. The solution was then sprayed onto the plants using a spray tower. After three weeks of incubation in a greenhouse, weed counts were calculated. Effective compound concentrations of 10, 5, and 2.5 g / ha were used. Three replicates were performed, and the average value was calculated. Representative data are listed in Table 2.

[0602] Table 2 Post-emergence herbicidal activity test of target compounds in the examples (g / mu)

[0603]

[0604]

[0605]

[0606]

[0607]

[0608] Biological activity evaluation:

[0609] The activity level standards for plant damage (i.e., growth control rate) are as follows:

[0610] Level 5: Growth control rate is above 85%;

[0611] Level 4: Growth control rate is greater than or equal to 60% and less than 85%;

[0612] Level 3: Growth control rate is greater than or equal to 40% and less than 60%;

[0613] Level 2: Growth control rate is greater than or equal to 20% and less than 40%;

[0614] Level 1: Growth control rate is greater than or equal to 5% and less than 20%;

[0615] Level 0: Growth control rate is less than 5%.

[0616] The above growth control rates are fresh weight control rates.

[0617] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Any simple modification, equivalent change, and modification made to the above embodiment without departing from the technical solution of the present invention and based on the technical essence of the present invention shall still fall within the scope of the technical solution of the present invention. Although the above embodiment has provided a detailed description of the present invention, it is only a part of the embodiment of the present invention, not all embodiments. Other embodiments can be obtained based on this embodiment without inventiveness, and these embodiments shall fall within the scope of protection of the present invention.

Claims

1. An N-phenylimine derivative, characterized in that: is a compound of formula 1; In Formula 1, the Het group is: In formula 1, X1 and X2 are independently F or Cl; R in Formula 1 1 is H; R in formula 1 is 2. The N-phenylimine derivative according to claim 1, characterized in that: The compound of formula 1 is selected from any one of formula 1-1 to formula 1-27:

3. The method for preparing an N-phenylimine derivative according to claim 1 or 2, characterized in that: The preparation method of the compound of formula 1 comprises the following steps: Mixing a compound represented by Formula 5, an alkali metal carbonate, a compound represented by Formula 6, and an organic solvent, and performing a nucleophilic substitution reaction to obtain a compound represented by Formula 1; The Het group, X1, X2 in Formula 5 and R, R1 in Formula 6 respectively match the structures of the compound of Formula 1 in Claim 1 or Claim 2, and X in Formula 6 is Cl or Br.

4. The preparation method according to claim 3, characterized in that The compound of the structure shown in Formula 5 is a compound of the structure shown in Formula 5-1. The preparation method of the compound of the structure shown in Formula 5-1 comprises the following steps: Mixing the compound of formula 11, an ethanol-water solution, ammonium chloride, and iron powder, and performing a reduction reaction to obtain a compound of formula 12; The compound of the structure represented by Formula 12, glacial acetic acid and a diketone compound are mixed and subjected to a nucleophilic substitution reaction to obtain a compound of the structure represented by Formula 5-1; the diketone compound is 4,5,6,7-tetrahydroisobenzofuran-1,3-dione; 5. The preparation method according to claim 3, characterized in that The preparation method of the compound of the structure shown in Formula 6 comprises the following steps: Mixing a compound of the structure represented by Formula 13, an organic solvent, and neutral hydroxylamine hydrochloride to carry out an amidoximation reaction to obtain a compound of the structure represented by Formula 14; Mixing the compound represented by Formula 14, the compound represented by Formula 15, triethylamine, and an organic solvent, and performing a ring-forming reaction to obtain a compound represented by Formula 6; R-CN formula 13, In formula 15, X is Cl or Br.

6. Use of the N-phenylimine derivative according to claim 1 or 2 or the N-phenylimine derivative prepared by the preparation method according to any one of claims 3 to 5 as an active ingredient of a herbicide, wherein the herbicide is a post-emergence herbicide for broad-leaved weeds.

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