N-phenyl phthalimide compound containing nicotinic acid fragment and ester group structure as well as preparation method and application of N-phenyl phthalimide compound

Abstract

The invention discloses an N-phenyl phthalimide compound containing a nicotinic acid fragment and an ester group structure as well as a preparation method and application of the N-phenyl phthalimide compound, and belongs to the field of herbicides. The technical problem that existing herbicides cannot give consideration to both herbicidal activity and use safety is solved. The structural general formula of the compound is shown as a formula (I) or a formula (II), wherein the formula (I) and the formula (II) are shown in the specification. The N-phenyl phthalimide compound containing the nicotinic acid fragment and the ester group structure provided by the invention has good inhibitory activity on PPO. The herbicidal composition has especially excellent herbicidal activity on morning glory, digitaria sanguinalis, amaranthus retroflexus, abutilon fiber and other weeds, especially has an excellent effect on dicotyledonous weeds, and the control effect is even superior to that of some commercially available commercial herbicides. The compound can be used as a PPO inhibitor. The weeding composition can also be prepared into a weeding agent for preventing and controlling crop weeds.

Description

An N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group, its preparation method and application. Technical Field

[0001] This invention belongs to the field of herbicides, specifically relating to an N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group, its preparation method, and its application. Background Technology

[0002] Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX. This reaction, primarily occurring in the chloroplasts and mitochondria of plant cells, is a crucial step in the biosynthetic pathways of chlorophyll and heme. PPO inhibitor herbicides prevent the conversion of protoporphyrinogen IX to protoporphyrin IX by competing for the enzyme's active site, leading to its accumulation in large quantities within the cell. The accumulated protoporphyrinogen IX is oxidized in the cytoplasm to generate photosensitive protoporphyrin IX; the latter can excite molecular oxygen to produce reactive oxygen species (ROS), triggering lipid peroxidation of the cell membrane, leading to membrane rupture and ultimately plant death. Currently, commercially available PPO inhibitors cover various structural types, including diphenyl ethers, pyrimidine diones, N-phenylphthalimides, oxadiazoles, thiadiazoles, triazolinones, and phenylpyrazoles. The development of contemporary PPO inhibitor herbicides faces many challenges. Due to long-term unreasonable use, problems such as environmental pollution, resistant weeds, phytotoxicity, and residues have emerged.

[0003] N-phenylphthalimide herbicides are among the PPO inhibitor herbicides developed in recent years. These herbicides are derived from the chemical skeleton of the insecticide pyrethroids, developed by introducing a benzene ring onto the nitrogen atom. Starting with the lead compound Chlorophthalim, researchers have successfully synthesized a series of derivatives by introducing heteroatoms into the benzene ring and various functional groups into the side chain. Although N-phenylphthalimide herbicides have certain advantages, their weed control spectrum remains relatively narrow, especially showing insufficient efficacy against certain monocotyledonous weeds. Therefore, structural innovation of N-phenylphthalimide herbicides remains an important research direction. Summary of the Invention

[0004] To overcome the above-mentioned technical defects, the present invention provides an N-phenylphthalimide compound containing nicotinic acid fragments and ester groups, which maintains high herbicidal activity while still having high safety for crops.

[0005] The technical solution of the present invention is as follows:

[0006] One objective of this invention is to provide an N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group, wherein the general structural formula of the compound is shown in formula (I) or formula (II) below:

[0007]

[0008] Formula (I)

[0009]

[0010] Formula (II)

[0011] in,

[0012] R1: 2-H or ;

[0013] R2: , or ;

[0014] R3: 2-F, 2-Cl, 2-Br, 4-Cl, 6-F, 6-Cl, 6-Br, Or 2,6-diCl.

[0015] A second objective of this invention is to provide a method for preparing N-phenylphthalimide compounds containing nicotinic acid fragments and ester groups, the method comprising the following steps:

[0016] Step 1: Dissolve 4-aminophenol, 2-methyl-4-aminophenol, 3-aminophenol, or 2-methyl-5-aminophenol in organic solvent one, then add compound a. After the reaction is complete, cool to room temperature, add distilled water, extract, wash, dry, and concentrate to obtain intermediate d or intermediate e; the structural formula of compound a is:

[0017]

[0018] Step 2: Compound f was dissolved in organic solvent 2, followed by the addition of intermediate d or intermediate e, and finally 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-dimethylaminopyridine. After the reaction was completed, the mixture was cooled to room temperature, and distilled water was added for extraction, washing, drying, and concentration. Column chromatography was used to purify the N-phenylphthalimide compound (I) or (II) containing nicotinic acid fragments and ester groups. The structural formula of compound f is:

[0019] , or .

[0020] Furthermore, in step one, the organic solvent is dimethyl sulfoxide or glacial acetic acid, preferably glacial acetic acid.

[0021] Furthermore, in step one, the molar ratio of compound a to 4-aminophenol, 2-methyl-4-aminophenol, 3-aminophenol, or 2-methyl-5-aminophenol is 1:1.

[0022] Furthermore, the reaction temperature in step one is 85-110℃, preferably 110℃.

[0023] Furthermore, in step two, the organic solvent two is dichloromethane or tetrahydrofuran, preferably tetrahydrofuran.

[0024] Furthermore, in step two, the molar ratio of compound f to intermediate d or intermediate e is 1:1.1.

[0025] Furthermore, in step two, the molar ratio of compound f to the activating reagent 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:2.

[0026] Furthermore, in step two, the molar ratio of compound f to catalyst 4-dimethylaminopyridine is 1:0.2.

[0027] Furthermore, the reaction temperature in step two is 25-45℃, preferably 30℃.

[0028] Furthermore, the eluent used in the column chromatography in step two is ethyl acetate-petroleum ether.

[0029] A third objective of this invention is to provide an N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group as an inhibitor of protoporphyrinogen oxidase (PPO).

[0030] The fourth objective of this invention is to provide an application of N-phenylphthalimide compounds containing nicotinic acid fragments and ester groups in weed control.

[0031] Furthermore, as mentioned above, the weeds are either monocotyledonous or dicotyledonous.

[0032] Furthermore, as mentioned above, the weeds are barnyard grass, crabgrass, goosegrass, morning glory, velvetleaf, or amaranth.

[0033] Furthermore, the application described above is carried out in the presence of crops, such as wheat, corn, rice, cotton, soybeans, or peanuts.

[0034] The fifth objective of this invention is to provide an application of an N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group as an active ingredient in the preparation of a herbal remedy for removing impurities.

[0035] Furthermore, as described above, the concentration of the active ingredient in the pharmaceutical preparation is 75-300 g ai / ha.

[0036] The advantages of this invention compared to existing technologies are as follows: By introducing nicotinic acid fragments, ester groups, and different substituents into the molecular structure, this invention optimizes electronic effects and steric hindrance, significantly improving weed control efficacy. In particular, it overcomes the deficiency of traditional N-phenylphthalimide herbicides in controlling monocotyledonous weeds, achieving highly efficient inhibition of monocotyledonous weeds such as barnyardgrass. The compounds of this invention exhibit good inhibitory activity against PPO (protoporphyrinogen oxidase), effectively controlling a variety of weeds, including monocotyledonous weeds (such as barnyardgrass, barnyardgrass, and goosegrass) and dicotyledonous weeds (such as morning glory, velvetleaf, and amaranth). Some excellent compounds (such as II-g10, II-h10, and II-h12) showed inhibition rates of ≥90% (++++ level) against all tested weeds at this dosage, with weed control effects comparable to or even better than the commercially available herbicide flumetsulam. Even at low application rates (75 g ai / ha), some compounds still maintained more than 50% inhibition activity against key weeds (such as morning glory and velvetleaf), reducing pesticide usage and environmental pressure, which aligns with the trend of green pesticide development. Attached Figure Description

[0037] Figure 1 shows the synthetic route of the N-phenylphthalimide compounds containing nicotinic acid fragments and ester groups in this invention;

[0038] Figure 2 shows the herbicidal activity of II-h10 at different application rates in Application Example 1.

[0039] Figure 3 shows the crop safety effect of II-h10 at an application rate of 300 g ai / ha in Application Example 3. Detailed Implementation

[0040] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0041] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials, reagents, methods, and instruments used are all conventional materials, reagents, methods, and instruments in the art, and can be obtained commercially by those skilled in the art.

[0042] The structures of the compounds in the following examples were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS).

[0043] Example 1

[0044] As shown in Figure 1, 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-4-chloropyridinium ester ( Preparation of -g1):

[0045] Step 1: Preparation of intermediate d

[0046] In a round-bottom flask, 20 mmol of 4-aminophenol, 20 mmol of 3,4,5,6-tetrahydrophthalic anhydride, and 40 mL of glacial acetic acid were added. The mixture was reacted at 110 °C for 6 hours, and the reaction was monitored by thin-layer chromatography (TLC). After the reaction was complete, the reaction solution was cooled to room temperature, and 200 mL of distilled water was added. The liquid phase was transferred to a separatory funnel, extracted with 60 mL × 3 ethyl acetate, and washed with 60 mL × 3 saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the ethyl acetate was removed by rotary evaporation to obtain intermediate d.

[0047] Step 2: Preparation of 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-4-chloropyridinium ester (I-g1)

[0048] In a round-bottom flask, intermediate d (10 mmol), 4-chloro-2-pyridinecarboxylic acid (11 mmol), 4-dimethylaminopyridine (DMAP, 2 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 20 mmol), and tetrahydrofuran (40 mL) were added. The mixture was stirred at 30 °C for 6 hours, and the reaction was monitored by thin-layer chromatography (TLC). After the reaction was complete, the reaction mixture was transferred to a separatory funnel, and distilled water (200 mL) was added. The mixture was extracted with ethyl acetate (60 mL × 3) and washed with saturated brine (60 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The product obtained by rotary evaporation was purified by column chromatography (ethyl acetate: petroleum ether = 1:3), and rotary evaporated again to finally obtain 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-4-chloropyridine ester. A light yellow solid, with a yield of 85%.

[0049] Product detection data are as follows: mp: 189.2-190.2℃; NMR (600 MHz, ) δ 8.74(d, J = 5.2 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 5.3, 2.0 Hz,1H), 7.48 - 7.42 (m, 2H), 7.37 - 7.31 (m, 2H), 2.43 (p, J = 2.9 Hz, 4H), 1.82(p, J = 3.0 Hz, 4H). NMR (151 MHz, ) δ 168.67, 161.47, 149.83,148.22, 147.54, 144.78, 140.86, 129.05, 126.67, 125.76, 125.40, 121.04,20.36, 19.14. HRMS calcd for [M+ ] , 383.0720, found 383.0796.

[0050] The structure of the obtained product, after characterization, is as follows: .

[0051] Example 2

[0052] 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-4-chloropyridinium ester ( Preparation of -g2):

[0053] The difference between this embodiment and Example 1 is that 4-aminophenol is replaced with 2-methyl-4-aminophenol in step 1. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-4-chloropyridinium ester is obtained as a pale yellow solid with a yield of 81%.

[0054] Product detection data are as follows: mp: 133.9-134.8℃; NMR (600 MHz, ) δ 8.74(d, J = 5.2 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 5.2, 2.0 Hz,1H), 7.31 - 7.19 (m, 4H), 2.41 (p, J = 3.0 Hz, 4H), 2.25 (s, 3H), 1.81 (p, J= 3.1 Hz, 4H). NMR (151 MHz, ) δ 168.76, 161.24, 149.96, 147.55,147.06, 144.66, 140.79, 130.04, 129.03, 127.41, 126.64, 125.31, 123.45,121.28, 20.33, 19.15, 15.42. HRMS calcd for [M + ] , 397.0877,found 397.0952.

[0055] The structure of the obtained product, after characterization, is as follows: .

[0056] Example 3

[0057] 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-4-chloropyridinium ester ( Preparation of -h1):

[0058] The difference between this example and Example 1 is that 4-aminophenol is replaced with 3-aminophenol in step 1. Other steps and parameters are the same as in Example 1. 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-4-chloropyridinium ester is obtained. It is a white solid with a yield of 78%.

[0059] Product detection data are as follows: mp: 139.5-140.4 ℃; NMR (600 MHz, ) δ 8.67(d, J = 5.2 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 5.2, 2.0 Hz,1H), 7.44 (t, J = 8.1 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.22 - 7.15 (m, 2H), 2.36 (p, J = 3.1 Hz, 4H), 1.79 - 1.71 (m, J = 3.4, 2.8 Hz, 4H). NMR (151 MHz, ) δ 168.40, 161.35, 149.87, 149.67, 147.59, 144.67, 140.72, 132.14,128.81, 126.63, 125.38, 122.07, 119.13, 117.66, 20.33, 19.14. HRMS calcd for[M + ] , 383.0720, found 383.0804.

[0060] The structure of the obtained product, after characterization, is as follows: .

[0061] Example 4

[0062] 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-4-chloropyridinium ester ( Preparation of -h2):

[0063] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-5-aminophenol in step 1. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-4-chloropyridinium ester is obtained as a pale yellow solid with a yield of 84%.

[0064] Product detection data are as follows: mp: 130.4-130.9℃; NMR (600 MHz, ) δ 8.74(d, J = 5.2 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 5.3, 2.0 Hz,1H), 7.35 (d, J = 8.8 Hz, 1H), 7.28 (p, J = 2.5 Hz, 2H), 2.41 (h, J = 3.1 Hz, 4H), 2.26 (s, 3H), 1.81 (h, J = 3.7 Hz, 4H). NMR (151 MHz, ) δ168.52, 161.03, 149.94, 148.11, 147.53, 144.64, 140.79, 130.30, 129.78,128.13, 126.61, 125.33, 122.32, 117.97, 20.31, 19.13, 15.05. HRMS calcd for[M + ] , 397.0877, found 397.0960.

[0065] The structure of the obtained product, after characterization, is as follows: .

[0066] Example 5

[0067] 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-chloropyridinium ester ( Preparation of -h3):

[0068] The difference between this example and Example 1 is that in step 1, 4-aminophenol is replaced with 2-methyl-5-aminophenol. In step 2, 4-chloro-2-pyridinecarboxylic acid is replaced with 6-chloro-2-pyridinecarboxylic acid. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-chloropyridine ester is obtained. It is a white solid with a yield of 88%.

[0069] Product detection data are as follows: mp: 137.7 -138.5℃; NMR (600 MHz, ) δ8.21 (dd, J = 7.6, 0.9 Hz, 1H), 7.89 (t, J = 7.8 Hz, 1H), 7.61 (dd, J = 8.0,0.9 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 2.2 Hz, 2H), 2.42 (p, J =2.9 Hz, 4H), 2.26 (s, 3H), 1.82 (h, J = 3.5 Hz, 4H). NMR (151 MHz, )δ 168.54, 160.84, 150.96, 148.17, 146.49, 140.78, 138.69, 130.25, 129.69,128.21, 127.61, 123.39, 122.27, 118.06, 20.31, 19.12, 15.07. HRMS calcd for[M + ] , 397.0877, found 397.0956.

[0070] The structure of the obtained product, after characterization, is as follows: .

[0071] Example 6

[0072] Preparation of 4-(1,3-dioxo-1,3,4-5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-2-fluoronicotinic acid ester (II-g1):

[0073] The difference between this example and Example 1 is that 4-chloro-2-pyridinecarboxylic acid is replaced with 2-fluoronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4-5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-2-fluoronicotinic acid ester is obtained. It is a white solid with a yield of 78%.

[0074] Product detection data are as follows: mp: 146.4-147.7℃; NMR (600 MHz, ) δ 8.54(ddd, J = 9.3, 7.5, 2.1 Hz, 1H), 8.50 - 8.45 (m, 1H), 7.47 - 7.41 (m, 2H), 7.38 (ddd, J = 7.6, 4.8, 1.4 Hz, 1H), 7.35 - 7.29 (m, 2H), 2.44 (h, J = 3.3Hz, 4H), 1.83 (p, J = 3.2 Hz, 4H). NMR (151 MHz, ) δ 168.68, 161.60,160.35 (d, J = 8.2 Hz), 159.94, 151.46, 147.95, 142.63, 140.87, 128.99,125.85, 121.01, 120.61 (d, J = 4.9 Hz), 112.26, 112.10, 20.32, 19.16. HRMScalcd for [M + ] , 367.1016, found 367.1098.

[0075] The structure of the obtained product, after characterization, is as follows: .

[0076] Example 7

[0077] Preparation of 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-2-bromonicotinic acid ester (II-g2):

[0078] The difference between this example and Example 1 is that 4-chloro-2-pyridinecarboxylic acid is replaced with 2-bromonicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-2-bromonicotinic acid ester is obtained. It is a white solid with a yield of 79%.

[0079] Product detection data are as follows: mp: 186.3-187.6℃; NMR (600 MHz, ) δ 8.56(dd, J = 4.8, 2.0 Hz, 1H), 8.27 (dd, J = 7.6, 2.0 Hz, 1H), 7.48 - 7.41 (m,3H), 7.38 - 7.32 (m, 2H), 2.44 (h, J = 3.3 Hz, 4H), 1.83 (hept, J = 4.5 Hz,4H). NMR (151 MHz, ) δ 168.66, 162.20, 151.57, 147.98, 140.88,140.10, 139.08, 129.08, 127.89, 125.91, 121.42, 120.92, 20.32, 19.17. HRMScalcd for [M+ ] , 427.0215, found 427.0292.

[0080] The structure of the obtained product, after characterization, is as follows: .

[0081] Example 8

[0082] Preparation of 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-fluoronicotinic acid ester (II-g3):

[0083] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-4-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 2-fluoronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-fluoronicotinic acid ester is obtained as a brown solid with a yield of 81%.

[0084] Product detection data are as follows: mp: 174.1-176.1℃; NMR (600 MHz, ) δ 8.55(ddd, J = 9.3, 7.5, 2.1 Hz, 1H), 8.48 (dd, J = 4.9, 2.0 Hz, 1H), 7.39 (ddd, J= 7.6, 4.8, 1.4 Hz, 1H), 7.31 - 7.22 (m, 3H), 2.43 (h, J = 3.4 Hz, 4H), 2.28 (s, 3H), 1.83 (h, J = 3.7 Hz, 4H). NMR (151 MHz, ) δ 170.15, 162.95,161.58 (d, J = 8.6 Hz), 161.29, 152.81, 152.71, 148.18, 144.03, 142.18,131.37, 130.29, 128.93, 124.86, 122.65, 122.01 (d, J = 4.8 Hz), 113.57,113.40, 21.70, 20.52, 16.80. HRMS calcd for [M + ] , 381.1172,found 381.1249.

[0085] The structure of the obtained product, after characterization, is as follows: .

[0086] Example 9

[0087] Preparation of 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-chloronicotinate (II-g4):

[0088] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-4-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 2-chloronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-chloronicotinic acid ester is obtained as a brown solid with a yield of 85%.

[0089] Product detection data are as follows: mp: 169.6-171.3℃; NMR (600 MHz, ) δ 8.59(dd, J = 4.8, 2.0 Hz, 1H), 8.37 (dd, J = 7.7, 2.0 Hz, 1H), 7.41 (dd, J = 7.7,4.8 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.26 - 7.21 (m, 2H), 2.41 (p, J = 3.0Hz, 4H), 2.28 (s, 3H), 1.82 - 1.80 (m, 4H). NMR (151 MHz, ) δ168.77, 161.48, 151.52, 149.54, 146.83, 140.83, 139.74, 130.05, 129.03,127.62, 125.07, 123.60, 121.26, 20.33, 19.16, 15.60. HRMS calcd for [M + ] , 397.0877, found 397.0953.

[0090] The structure of the obtained product, after characterization, is as follows: .

[0091] Example 10

[0092] Preparation of 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-bromonicotinic acid ester (II-g5):

[0093] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-4-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 2-bromonicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-bromonicotinic acid ester is obtained as a yellow solid with a yield of 79%.

[0094] Product detection data are as follows: mp: 152.7-154.6℃; NMR (600 MHz, ) δ 8.57(dd, J = 4.7, 2.0 Hz, 1H), 8.30 (dd, J = 7.7, 2.0 Hz, 1H), 7.44 (dd, J = 7.7,4.8 Hz, 1H), 7.30 (q, J = 1.2 Hz, 1H), 7.26 (d, J = 1.5 Hz, 2H), 2.43 (p, J =3.1 Hz, 4H), 2.30 (s, 3H), 1.82 (hept, J = 4.3 Hz, 4H). NMR (151 MHz, ) δ 168.76, 161.93, 151.59, 146.80, 140.83, 140.13, 139.06, 130.05,129.06, 127.81, 127.62, 123.61, 121.43, 121.23, 20.33, 19.16, 15.63. HRMScalcd for [M + ] , 441.0372, found 441.0445.

[0095] The structure of the obtained product, after characterization, is as follows: .

[0096] Example 11

[0097] Preparation of 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-6-chloronicotinate (II-g6):

[0098] The difference between this example and Example 1 is that 4-chloro-2-pyridinecarboxylic acid is replaced with 6-chloronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-6-chloronicotinic acid ester is obtained. It is a white solid with a yield of 79%.

[0099] Product detection data are as follows: mp: 198.0-198.8℃; NMR (600 MHz, ) δ 9.16(dd, J = 2.5, 0.8 Hz, 1H), 8.39 (dd, J = 8.3, 2.4 Hz, 1H), 7.50 (dd, J = 8.4,0.8 Hz, 1H), 7.46 - 7.44 (m, 2H), 7.34 - 7.28 (m, 2H), 2.43 (h, J = 2.5 Hz, 4H), 1.83 (dq, J = 6.1, 2.7 Hz, 4H). NMR (151 MHz, ) δ 169.70,162.82, 156.46, 151.70, 148.93, 141.92, 140.09, 130.08, 126.91, 124.44 (d, J= 5.5 Hz), 122.04, 21.35, 20.20. HRMS calcd for [M + ] ,383.0720, found 383.0800.

[0100] The structure of the obtained product, after characterization, is as follows: .

[0101] Example 12

[0102] Preparation of 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-6-bromonicotinic acid ester (II-g7):

[0103] The difference between this example and Example 1 is that 4-chloro-2-pyridinecarboxylic acid is replaced with 6-bromonicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-6-bromonicotinic acid ester is obtained as a white solid with a yield of 81%.

[0104] Product detection data are as follows: mp: 209.1-209.9℃; NMR (600 MHz, ) δ 9.14- 9.11 (m, 1H), 8.27 (dd, J = 8.3, 2.4 Hz, 1H), 7.67 (dd, J = 8.2, 0.8 Hz,1H), 7.48 - 7.42 (m, 2H), 7.33 - 7.27 (m, 2H), 2.44 (h, J = 3.3 Hz, 4H), 1.86- 1.80 (m, J = 4.4 Hz, 4H). NMR (151 MHz, ) δ 168.66, 161.95,150.86, 147.88, 146.63, 140.89, 138.59, 129.07, 127.30, 125.87, 123.72,120.99, 20.32, 19.17. HRMS calcd for [M+ ] , 427.0215, found427.0290.

[0105] The structure of the obtained product, after characterization, is as follows: .

[0106] Example 13

[0107] Preparation method of 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-6-(trifluoromethyl)nicotinate (II-g8):

[0108] The difference between this example and Example 1 is that 4-chloro-2-pyridinecarboxylic acid is replaced with 6-(trifluoromethyl)nicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-6-(trifluoromethyl)nicotinic acid ester is obtained as a pale yellow solid with a yield of 72%.

[0109] Product detection data are as follows: mp: 132.8-133.4℃; NMR (600 MHz, ) δ 9.47(d, J = 2.0 Hz, 1H), 8.64 (dd, J = 8.1, 2.1 Hz, 1H), 7.86 (dd, J = 8.1, 0.9Hz, 1H), 7.50 - 7.44 (m, 2H), 7.36 - 7.30 (m, 2H), 2.44 (h, J = 3.3 Hz, 4H), 1.87 - 1.80 (m, J = 4.4 Hz, 4H). NMR (151 MHz, ) δ 168.65, 161.39,150.78 (t, J = 35.3 Hz), 150.44, 147.80, 140.91, 138.34, 129.22, 126.94,125.92, 120.94, 119.37 (q, J = 2.7 Hz), 20.31, 19.17. HRMS calcd for [M + ] , 417.0984, found 417.1059.

[0110] The structure of the obtained product, after characterization, is as follows: .

[0111] Example 14

[0112] 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-fluoronicotinate ( Preparation method of -g9):

[0113] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-4-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 6-fluoronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-fluoronicotinic acid ester is obtained as a brown solid with a yield of 70%.

[0114] Product detection data are as follows: mp: 137.8-138.4℃; NMR (600 MHz, ) δ 9.09(d, J = 2.4 Hz, 1H), 8.58 (ddd, J = 8.5, 7.5, 2.5 Hz, 1H), 7.30 (d, J = 2.5Hz, 1H), 7.29 - 7.25 (m, 1H), 7.23 (d, J = 8.6 Hz, 1H), 2.44 (h, J = 3.3 Hz,4H), 2.26 (s, 3H), 1.87 - 1.79 (m, 4H). NMR (151 MHz, ) δ 168.78,166.03, 164.40, 161.24, 149.98 (d, J = 16.7 Hz), 146.75, 142.12 (d, J = 9.4Hz), 140.83, 130.03, 128.97, 127.57, 123.57, 122.71 (d, J = 4.6 Hz), 121.35,109.04, 108.79, 20.33, 19.16, 15.40. HRMS calcd for [M + ] ,381.1172, found 381.1251.

[0115] The structure of the obtained product, after characterization, is as follows: .

[0116] Example 15

[0117] 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-chloronicotinate ( Preparation of -g10):

[0118] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-4-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 6-chloronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-chloronicotinic acid ester is obtained as a brownish-red solid with a yield of 86%.

[0119] Product detection data are as follows: mp: 148.4-149.1℃; NMR (600 MHz, ) δ 9.19(d, J = 2.4 Hz, 1H), 8.41 (dd, J = 8.3, 2.4 Hz, 1H), 7.52 (d, J = 8.3 Hz,1H), 7.30 (d, J = 2.5 Hz, 1H), 7.27 (dd, J = 5.6, 3.0 Hz, 1H), 7.23 (d, J =8.6 Hz, 1H), 2.44 (h, J = 3.2 Hz, 4H), 2.25 (s, 3H), 1.83 (hept, J = 4.4 Hz, 4H). NMR (151 MHz, ) δ 168.76, 161.48, 155.46, 150.63, 146.71,140.83, 139.05, 129.99, 129.01, 127.56, 123.56, 123.48, 123.29, 121.31,20.33, 19.16, 15.40. HRMS calcd for [M + ] , 397.0877, found397.0952.

[0120] The structure of the obtained product, after characterization, is as follows: .

[0121] Example 16

[0122] 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-bromonicotinic acid ester ( Preparation of -g11):

[0123] The difference between this example and Example 1 is that in step 1, 4-aminophenol is replaced with 2-methyl-4-aminophenol. In step 2, 4-chloro-2-pyridinecarboxylic acid is replaced with 6-bromonicotinic acid. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-bromonicotinic acid ester is obtained as a brown solid with a yield of 83%.

[0124] Product detection data are as follows: mp: 155.5-156.5℃; NMR (600 MHz, ) δ 9.16(d, J = 2.4 Hz, 1H), 8.30 (dd, J = 8.3, 2.4 Hz, 1H), 7.69 (d, J = 8.3 Hz,1H), 7.30 (d, J = 2.4 Hz, 1H), 7.28 - 7.26 (m, 1H), 7.23 (d, J = 8.6 Hz, 1H), 2.44 (h, J = 3.3 Hz, 4H), 2.25 (s, 3H), 1.84 (hept, J = 4.2 Hz, 4H). NMR (151 MHz, ) δ 170.13, 163.02, 152.19, 148.07, 148.04, 142.20, 139.96,131.35, 130.38, 128.94, 128.73, 124.97, 124.94, 122.67, 21.69, 20.53, 16.77.HRMS calcd for [M + ] , 441.0372, found 441.0451.

[0125] The structure of the obtained product, after characterization, is as follows: .

[0126] Example 17

[0127] 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-(trifluoromethyl)nicotinate ( Preparation of -g12):

[0128] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-4-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 6-(trifluoromethyl)nicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-(trifluoromethyl)nicotinic acid ester is obtained as a brown solid with a yield of 74%.

[0129] Product detection data are as follows: mp: 164.1-165.3℃; NMR (600 MHz, ) δ 9.52(d, J = 2.0 Hz, 1H), 8.68 (dd, J = 8.3, 2.1 Hz, 1H), 7.90 (d, J = 8.1 Hz,1H), 7.33 (d, J = 2.4 Hz, 1H), 7.30 (dd, J = 8.6, 2.5 Hz, 1H), 7.28 (d, J =6.1 Hz, 1H), 2.46 (h, J = 3.0 Hz, 4H), 2.28 (s, 3H), 1.85 (p, J = 3.0 Hz, 4H). NMR (151 MHz, ) δ 169.79, 162.11, 151.95 (q, J = 35.3 Hz), 151.43, 147.66, 141.89, 139.40, 130.96, 130.19, 128.65, 127.87, 124.65,122.27, 120.48 (q, J = 2.7 Hz), 120.14, 21.35, 20.19, 16.43. HRMS calcd for[M + ] , 431.1140, found 431.1213.

[0130] The structure of the obtained product, after characterization, is as follows: .

[0131] Example 18

[0132] 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-2,6-dichloronicotinate ( Preparation of -g13):

[0133] The difference between this example and Example 1 is that 4-chloro-2-pyridinecarboxylic acid is replaced with 2,6-dichloronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-2,6-dichloronicotinic acid ester is obtained as a white solid with a yield of 71%.

[0134] Product detection data are as follows: mp: 147.2-148.5℃; NMR (600 MHz, ) δ 8.34(d, J = 8.1 Hz, 1H), 7.44 (dd, J = 12.0, 8.6 Hz, 3H), 7.32 (d, J = 8.3 Hz, 2H), 2.43 (s, 4H), 1.83 (s, 4H). NMR (151 MHz, ) δ 168.64, 160.84,152.68, 149.40, 147.81, 141.89, 140.90, 129.17, 125.90, 123.49, 122.02,120.88, 20.31, 19.16. HRMS calcd for [M+ ] , 417.0331, found417.0402.

[0135] The structure of the obtained product, after characterization, is as follows: .

[0136] Example 19

[0137] 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2,6-dichloronicotinate ( Preparation of -g14):

[0138] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-4-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 2,6-dichloronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 4-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2,6-dichloronicotinic acid ester is obtained as a light brown solid with a yield of 74%.

[0139] Product detection data are as follows: mp: 144.4-145.2℃; NMR (600 MHz, ) δ 8.35(d, J = 8.1 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.24(d, J = 2.6 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 2.42 (h, J = 3.4 Hz, 4H), 2.26 (s, 3H), 1.81 (p, J = 3.1 Hz, 4H). NMR (151 MHz, ) δ 168.75, 160.66,152.70, 149.37, 146.68, 141.88, 140.85, 129.95, 129.13, 127.63, 123.60,123.46, 122.05, 121.20, 20.33, 19.16, 15.58. HRMS calcd for [M + ] , 431.0487, found 431.0560.

[0140] The structure of the obtained product, after characterization, is as follows: .

[0141] Example 20

[0142] 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-2-chloronicotinate ( Preparation of -h1):

[0143] The difference between this example and Example 1 is that 4-aminophenol is replaced with 3-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 2-chloronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-2-chloronicotinic acid ester is obtained. It is a white solid with a yield of 79%.

[0144] Product detection data are as follows: mp: 155.1-156.4℃; NMR (600 MHz, ) δ 8.52(dd, J = 4.8, 2.0 Hz, 1H), 8.30 (dd, J = 7.7, 2.0 Hz, 1H), 7.47 - 7.41 (m,1H), 7.34 (dd, J = 7.7, 4.8 Hz, 1H), 7.31 - 7.28 (m, 2H), 7.17 (dt, J = 8.4,1.3 Hz, 1H), 2.39 - 2.32 (m, 4H), 1.75 (hept, J = 4.2 Hz, 4H). NMR (151MHz, ) δ 168.42, 161.46, 151.51, 149.63, 149.42, 140.93, 139.78,132.17, 128.71, 124.99, 122.23, 121.22, 119.07, 117.61, 20.29, 19.15. HRMScalcd for [M + ] , 383.0720, found 383.0808.

[0145] The structure of the obtained product, after characterization, is as follows: .

[0146] Example 21

[0147] 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-fluoronicotinate ( Preparation of -h2):

[0148] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-5-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 2-fluoronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-fluoronicotinic acid ester is obtained. It is a white solid with a yield of 78%.

[0149] Product detection data are as follows: mp: 121.4-123.4℃; NMR (600 MHz, ) δ 8.54(ddd, J = 9.3, 7.5, 2.0 Hz, 1H), 8.48 (dd, J = 4.9, 2.0 Hz, 1H), 7.38 (ddd, J= 7.5, 4.9, 1.5 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 7.6, 2.7 Hz, 1H), 2.41 (h, J = 3.4 Hz, 4H), 2.27 (s, 3H), 1.81(hept, J = 4.2 Hz, 4H). NMR (151 MHz, ) δ 169.93, 162.96, 161.96 -160.76 (m), 152.75 (d, J = 15.4 Hz), 149.19, 144.03, 142.18, 131.70, 131.02,129.51, 123.77, 122.00 (d, J = 4.9 Hz), 119.43, 113.45 (d, J = 24.7 Hz), 21.68, 20.50, 16.44. HRMS calcd for [M + ] , 381.1172, found381.1252.

[0150] The structure of the obtained product, after characterization, is as follows: .

[0151] Example 22

[0152] 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-chloronicotinate ( Preparation of -h3):

[0153] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-5-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 2-chloronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-chloronicotinic acid ester is obtained. It is a white solid with a yield of 85%.

[0154] Product detection data are as follows: mp: 122.9-123.6℃; NMR (600 MHz, ) δ 8.59(dd, J = 4.8, 2.0 Hz, 1H), 8.37 (dd, J = 7.7, 2.0 Hz, 1H), 7.40 (dd, J = 7.7,4.8 Hz, 1H), 7.34 (dt, J = 7.9, 0.8 Hz, 1H), 7.29 - 7.23 (m, 2H), 2.41 (p, J= 3.3 Hz, 4H), 2.27 (s, 3H), 1.84 - 1.76 (m, 4H). NMR (151 MHz, ) δ168.56, 161.25, 151.50, 149.58, 147.85, 140.83, 139.77, 130.39, 129.76,128.18, 124.99, 122.51, 121.23, 118.01, 20.31, 19.13, 15.24. HRMS calcd for[M + ] , 397.0877, found 397.0960.

[0155] The structure of the obtained product, after characterization, is as follows: .

[0156] Example 23

[0157] 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-bromonicotinic acid ester ( Preparation of -h4):

[0158] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-5-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 2-bromonicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-bromonicotinic acid ester is obtained. It is a white solid with a yield of 81%.

[0159] Product detection data are as follows: mp: 143.3-143.5℃; NMR (600 MHz, ) δ 8.55(dd, J = 4.8, 1.9 Hz, 1H), 8.29 (dd, J = 7.8, 2.0 Hz, 1H), 7.42 (dd, J = 7.7,4.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.24 (d, J =2.3 Hz, 1H), 2.40 (h, J = 3.1 Hz, 4H), 2.27 (s, 3H), 1.80 (p, J = 2.9 Hz, 4H). NMR (151 MHz, ) δ 168.55, 161.70, 151.59, 147.83, 140.84,140.19, 139.08, 130.40, 129.78, 128.18, 127.71, 122.54, 121.41, 117.98,20.31, 19.14, 15.27. HRMS calcd for [M + ] , 441.0372, found441.0449.

[0160] The structure of the obtained product, after characterization, is as follows: .

[0161] Example 24

[0162] 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-6-chloronicotinate ( Preparation of -h5):

[0163] The difference between this example and Example 1 is that 4-aminophenol is replaced with 3-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 6-chloronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-6-chloronicotinic acid ester is obtained. It is a white solid with a yield of 83%.

[0164] Product detection data are as follows: mp: 100.5-101.2℃; NMR (600 MHz, ) δ 9.09(dd, J = 2.4, 0.7 Hz, 1H), 8.32 (dd, J = 8.3, 2.4 Hz, 1H), 7.47 - 7.43 (m,1H), 7.43 - 7.42 (m, 1H), 7.30 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H), 7.28 (t, J =2.1 Hz, 1H), 7.14 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 2.36 (h, J = 2.5 Hz, 4H), 1.76 (hept, J = 4.5 Hz, 4H). NMR (151 MHz, ) δ 168.42, 161.64,155.42, 150.67, 149.34, 140.94, 139.04, 132.17, 128.73, 123.42, 123.38,122.14, 119.08, 117.62, 20.29, 19.15. HRMS calcd for [M + ] ,383.0720, found 383.0804.

[0165] The structure of the obtained product, after characterization, is as follows: .

[0166] Example 25

[0167] 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-6-(trifluoromethyl)nicotinate ( Preparation of -h6):

[0168] The difference between this example and Example 1 is that 4-aminophenol is replaced with 3-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 6-(trifluoromethyl)nicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)phenyl-6-(trifluoromethyl)nicotinic acid ester is obtained as a pale yellow solid with a yield of 75%.

[0169] Product detection data are as follows: mp: 132.8-133.9℃; NMR (600 MHz, ) δ 9.46(d, J = 2.0 Hz, 1H), 8.64 (dd, J = 8.1, 2.1 Hz, 1H), 7.86 (dd, J = 8.2, 0.9Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.39 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H), 7.37(t, J = 2.1 Hz, 1H), 7.22 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 2.44 (h, J = 3.3Hz, 4H), 1.83 (dq, J = 6.1, 2.8 Hz, 4H). NMR (151 MHz, ) δ 168.41,161.26, 150.88 (q, J = 35.1 Hz), 150.44, 149.26, 140.97, 138.33, 132.25,128.80, 126.93, 122.29, 120.93, 119.37 (q, J = 2.7 Hz), 118.98, 117.54,20.29, 19.16. HRMS calcd for [M + ] , 417.0984, found417.1059.

[0170] The structure of the obtained product, after characterization, is as follows: .

[0171] Example 26

[0172] 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-fluoronicotinate ( Preparation of -h7):

[0173] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-5-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 6-fluoronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-fluoronicotinic acid ester is obtained as a yellow solid with a yield of 78%.

[0174] Product detection data are as follows: mp: 105.6-106.9℃; NMR (600 MHz, ) δ 9.06(d, J = 2.4 Hz, 1H), 8.54 (ddd, J = 8.5, 7.5, 2.5 Hz, 1H), 7.37 - 7.31 (m,1H), 7.25 (d, J = 9.5 Hz, 2H), 7.07 (dd, J = 8.5, 2.8 Hz, 1H), 2.40 (h, J =3.3 Hz, 4H), 2.23 (s, 3H), 1.80 (hept, J = 4.3 Hz, 4H). NMR (151 MHz, ) δ 168.56, 166.02, 164.38, 161.08, 149.99 (d, J = 16.8 Hz), 147.75,142.11 (d, J = 9.6 Hz), 140.83, 130.35, 129.74, 128.13, 122.40, 118.08,108.90 (d, J = 37.6 Hz), 20.30, 19.13, 15.03. HRMS calcd for [M + ] , 381.1172, found 381.1251.

[0175] The structure of the obtained product, after characterization, is as follows: .

[0176] Example 27

[0177] 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-chloronicotinate ( Preparation of -h8):

[0178] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-5-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 6-chloronicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-chloronicotinic acid ester is obtained. It is a white solid with a yield of 83%.

[0179] Product detection data are as follows: mp: 113.2-115.2℃; NMR (600 MHz, ) δ 9.16(d, J = 2.4 Hz, 1H), 8.38 (dd, J = 8.3, 2.4 Hz, 1H), 7.49 (d, J = 8.3 Hz,1H), 7.34 (d, J = 8.0 Hz, 1H), 7.25 (s, 2H), 2.40 (h, J = 3.1 Hz, 4H), 2.22(s, 3H), 1.80 (p, J = 2.9 Hz, 4H). NMR (151 MHz, ) δ 168.55, 161.32,155.44, 150.63, 147.72, 140.84, 139.05, 130.36, 129.75, 128.09, 123.48,123.26, 122.43, 118.03, 20.30, 19.13, 15.03. HRMS calcd for [M + ] , 397.0877, found 397.0960.

[0180] The structure of the obtained product, after characterization, is as follows: .

[0181] Example 28

[0182] 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-bromonicotinic acid ester ( Preparation of -h9):

[0183] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-5-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 6-bromonicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-bromonicotinic acid ester is obtained as a yellow solid with a yield of 79%.

[0184] Product detection data are as follows: mp: 135.9-137.2℃; NMR (600 MHz, ) δ 9.12(d, J = 2.4 Hz, 1H), 8.26 (dd, J = 8.3, 2.4 Hz, 1H), 7.65 (d, J = 8.3 Hz,1H), 7.33 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 1.5 Hz, 2H), 2.39 (h, J = 3.3 Hz, 4H), 2.22 (s, 3H), 1.80 (hept, J = 4.2 Hz, 4H). NMR (151 MHz, ) δ169.92, 162.86, 152.21, 149.08, 148.02, 142.21, 139.96, 131.74, 131.11,129.45, 128.72, 124.95, 123.81, 119.39, 21.67, 20.50, 16.40. HRMS calcd for[M + ] , 441.0372, found 441.0447.

[0185] The structure of the obtained product, after characterization, is as follows: .

[0186] Example 29

[0187] 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-(trifluoromethyl)nicotinate ( Preparation of -h10):

[0188] The difference between this example and Example 1 is that in step 1, 4-aminophenol is replaced with 2-methyl-5-aminophenol. In step 2, 4-chloro-2-pyridinecarboxylic acid is replaced with 6-(trifluoromethyl)nicotinic acid. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-6-(trifluoromethyl)nicotinic acid ester is obtained. It is a white solid with a yield of 76%.

[0189] Product detection data are as follows: mp: 136.2-137.4℃; NMR (600 MHz, ) δ 9.49(d, J = 2.0 Hz, 1H), 8.67 - 8.63 (m, 1H), 7.87 (dd, J = 8.1, 0.9 Hz, 1H), 7.37 (dd, J = 8.7, 0.8 Hz, 1H), 7.29 (dq, J = 4.0, 2.1 Hz, 2H), 2.42 (h, J =3.3 Hz, 4H), 2.25 (s, 3H), 1.82 (dq, J = 6.1, 2.7 Hz, 4H). NMR (151 MHz, ) δ 168.54, 160.93, 150.91 (d, J = 35.3 Hz), 150.41, 147.65, 140.87,138.36, 130.44, 129.82, 127.99, 126.81, 122.57, 120.92, 119.44 (q, J = 2.7Hz), 117.94, 20.30, 19.14, 15.02. HRMS calcd for [M + ] ,431.1140, found 431.1217.

[0190] The structure of the obtained product, after characterization, is as follows: .

[0191] Example 30

[0192] 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2,6-dichloronicotinate ( Preparation of -h11):

[0193] The difference between this example and Example 1 is that in step 1, 4-aminophenol is replaced with 2-methyl-5-aminophenol. In step 2, 4-chloro-2-pyridinecarboxylic acid is replaced with 2,6-dichloronicotinic acid. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2,6-dichloronicotinic acid ester is obtained. It is a yellow solid with a yield of 78%.

[0194] Product detection data are as follows: mp: 119.2-119.8℃; NMR (600 MHz, ) δ 8.34(d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.26- 7.23 (m, 2H), 2.39 (h, J = 3.4 Hz, 4H), 2.24 (s, 3H), 1.79 (p, J = 3.4 Hz, 4H). NMR (151 MHz, ) δ 168.54, 160.44, 152.69, 149.40, 147.71,141.90, 140.85, 130.43, 129.79, 128.05, 123.38, 122.57, 122.04, 117.91,20.30, 19.13, 15.21. HRMS calcd for [M + ] , 431.0487, found431.0562.

[0195] The structure of the obtained product, after characterization, is as follows: .

[0196] Example 31

[0197] Preparation of 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-fluoroisonicotinic acid ester (II-h12):

[0198] The difference between this example and Example 1 is that 4-aminophenol is replaced with 2-methyl-5-aminophenol in step 1, and 4-chloro-2-pyridinecarboxylic acid is replaced with 2-fluoroisonicotinic acid in step 2. Other steps and parameters are the same as in Example 1. 5-(1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindol-2-yl)-2-methylphenyl-2-fluoroisonicotinic acid ester is obtained as a pale yellow solid with a yield of 81%.

[0199] Product detection data are as follows: mp: 124.3-125.8℃; NMR (600 MHz, ) δ 8.46(d, J = 5.1 Hz, 1H), 7.91 (dt, J = 5.1, 1.5 Hz, 1H), 7.66 (dt, J = 2.2, 0.9Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.29 (dd, J = 8.1, 2.1 Hz, 1H), 7.27 (d, J= 2.1 Hz, 1H), 2.45 - 2.37 (m, J = 3.7 Hz, 4H), 2.24 (s, 3H), 1.81 (hept, J =4.2 Hz, 4H). NMR (151 MHz, ) δ 169.89, 166.19 - 159.92 (m), 149.40,149.30, 149.03, 142.23, 131.80, 131.20, 129.28, 123.93, 121.46 (d, J = 4.7Hz), 119.19, 110.75, 110.49, 21.67, 20.50, 16.35. HRMS calcd for [M + ] , 381.1172, found 381.1257.

[0200] The structure of the obtained product, after characterization, is as follows: .

[0201] Application Example 1

[0202] Tests to determine the herbicidal activity of the compounds in Examples 1-31:

[0203] To investigate the control effect of the compound on weeds, common weeds, namely barnyard grass, crabgrass, goosegrass, morning glory, velvetleaf, and amaranth, were selected for the experiment.

[0204] Weed cultivation method: Fill a small flowerpot (r = 4 cm, h = 8 cm) with about 6 cm of potting soil, moisten it completely with water, then put in the weed seeds for the test, cover with about 2 cm of potting soil, and spray the surface with water. Place in an artificial climate chamber and wait for it to grow. Cultivate at 28℃, 70% humidity, and 12 hours of light and 12 hours of darkness in a cycle.

[0205] Preparation of the target compound emulsion: Weigh 15 mg of the target compounds from Examples 1-31 and dissolve them separately in 1 mL of N,N-dimethylformamide (DMF). Add 1 drop of Tween-80 (T-80) as an emulsifier. Dissolve the emulsion in DMF in a 10 mL volumetric flask to obtain a solution with a target compound concentration of 1.5 g / L. The commercially available PPO herbicide flumetsulam was used as a control, and a DMF solution containing only T-80 and no target compound was used as a blank control.

[0206] When monocotyledonous weeds reached the single-leaf stage and dicotyledonous weeds reached the two-leaf stage, the stems and leaves of the weeds were sprayed with herbicide at concentrations of 75 g ai / ha, 150 g ai / ha, and 300 g ai / ha, respectively. A commercially available PPO herbicide, flufenacet, was used as a control group. Most weed plants showed obvious symptoms of dehydration, leaf curling, burning, and yellowing 12 hours after application, and bleaching and death occurred 48 hours later.

[0207] As shown in Table 1, most target compounds exhibited better inhibition of dicotyledonous weeds than monocotyledonous weeds, and also showed high inhibition of the monocotyledonous weed *Digitaria sanguinalis*. Most target compounds showed over 80% inhibition activity against weeds at an application rate of 300 g ai / ha, and even at a low application rate of 75 g ai / ha, some compounds still showed high weed inhibition. Analysis of Table 1 shows that the herbicidal activity of the target compounds is closely related to the electronic effects, steric hindrance, and substitution positions in their molecular structure. The electronic characteristics of the substituents on the pyridine ring are the key factors determining activity; strong electron-withdrawing groups (such as...) (-F) can significantly enhance activity, and the enhancement order is as follows: >-F > -Cl >-Br. For example, containing The compound (II-h10) exhibits higher activity than its analogues containing -F or -Cl, likely due to the electron-withdrawing group reducing the electron density of the pyridine ring. Regarding steric effects, the position of the substituent is equally crucial; compounds substituted at the 6-position (e.g., II-g9) generally show better activity than isomers substituted at the 2-position (e.g., II-g3). Furthermore, the substitution pattern of the linking group on the benzene ring significantly influences activity; meta-substituted halogenated nicotinamide derivatives (e.g., II-h10) are typically more active than para-substituted isomers (e.g., II-g12), primarily because the meta configuration reduces steric hindrance and promotes binding. Simultaneously, the introduction of a methyl group at the 2-position of the benzene ring (e.g., II-h10) can modulate the electron density of the benzene ring through its weak electron-donating effect. Compounds II-g10, II-h10, and II-h12 demonstrate excellent weed-suppressing ability, comparable to or slightly superior to flumetsulam.

[0208] Table 1. Herbicidal activity of compounds in greenhouses

[0209]

[0210]

[0211]

[0212]

[0213] Note: Herbicidal activity rating scale (inhibition percentage): ++++, ≥90%; +++, 80-89%; ++, 60-79%; +, 50-59%; -, <50%.

[0214] Application Example 2

[0215] Example of PPO inhibitory activity test:

[0216] Plant tissue sample processing method: Wash barnyard grass leaves in 50 mL of ice-cold PBS and dry with filter paper. Add 9 times the volume of homogenizing medium to a homogenization tube at a weight (g):volume (mL) ratio of 1:9. Under ice-water bath conditions, cut the tissue blocks and grind them thoroughly to prepare a 10% homogenate. Centrifuge the prepared 10% homogenate at 6000 rpm for 20 minutes in a high-speed refrigerated centrifuge, and collect the supernatant for analysis.

[0217] Homogenization medium: Tris-HCl phosphate buffer (PBS), with a Tris-HCl concentration of 0.05 mol / L and a pH of 7.4.

[0218] The concentration of PPO enzyme in compounds with good herbicidal activity was determined using a plant protoporphyrinogen oxidase (PPOX) ELISA kit. The results are shown in Table 2. By measuring the inhibitory ability of the compounds on PPO enzyme, it was found that the herbicidal activity of the target compounds was almost consistent with the in vitro PPO inhibitory activity results.

[0219] Table 2. Effects of compound PPO enzyme activity inhibition assay

[0220]

[0221] Application Example 3

[0222] Crop safety trials:

[0223] This embodiment illustrates the safety of the N-phenylphthalimide compounds containing nicotinic acid fragments and ester groups of the present invention for crops. Target crops: wheat, corn, rice, cotton, soybean, and peanut.

[0224] Crop planting methods: Wheat, corn, rice, soybean, and peanut seeds need to be soaked in warm water for 12 hours before planting and germinated at 25℃ for 24 hours. Cotton seeds need to be exposed to sunlight for 2-4 days beforehand. Then, select 10 uniform and well-germinated crop seeds from each crop, fill a small flowerpot (r = 4 cm, h = 8 cm) with about 6 cm of potting soil, moisten it completely with water, place the test seeds in the pot, cover the top with about 2 cm of potting soil, spray the surface with water, and place it in an artificial climate chamber to wait for growth. The humidity is 70%, the temperature is 28℃, and the light and dark cycles are repeated for 12 hours each.

[0225] Preparation of target compound emulsion: Weigh 15 mg of the target compound from Example 29, dissolve it in N,N-dimethylformamide (DMF), add 1 drop of Tween-80 (T-80) as an emulsifier, and dilute to volume with DMF in a 10 mL volumetric flask to obtain a solution with a target compound concentration of 1.5 g / L.

[0226] When the crop reached the 3-leaf stage, the herbicide was sprayed at concentrations of 150 g ai / ha and 300 g ai / ha, respectively, with the commercially available PPO herbicide flumetsulam as a control. Crop growth was continuously monitored after application.

[0227] As shown in Table 3, all of the above compounds can be used as herbicides. At an application rate of 300 gai / ha, soybeans, cotton, and wheat exhibited high tolerance to compound II-h10, with crop safety exceeding that of the commercially available herbicide flumetsulam.

[0228] Table 3. Safety of Compound II-h10 and Flumetsulam to Crops

[0229]

[0230] The above description is merely a preferred embodiment of the present invention. These specific embodiments are different implementations based on the overall concept of the present invention, and the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. An N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group, characterized in that, The general structural formula of the compound is shown in formula (I) or formula (II) below: Equation (I) Formula (II) where R1: 2-H or ；R2： 、 or ;R3: 2-F、2-Cl、2-Br、4-Cl、6-F、6-Cl、6-Br、 Or 2,6-diCl.

2. The method for preparing an N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group structure as described in claim 1, characterized in that, The steps are as follows: Step 1: Dissolve 4-aminophenol, 2-methyl-4-aminophenol, 3-aminophenol, or 2-methyl-5-aminophenol in organic solvent one, then add compound a. After the reaction is complete, cool to room temperature, add distilled water, extract, wash, dry, and concentrate to obtain intermediate d or intermediate e; wherein, the structural formula of compound a is: Step 2: Compound f is dissolved in organic solvent 2, followed by the addition of intermediate d or intermediate e, and finally 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-dimethylaminopyridine. After the reaction is complete, the mixture is cooled to room temperature, distilled water is added, and the mixture is extracted, washed, dried, and concentrated. Column chromatography is used to purify the mixture to obtain N-phenylphthalimide compounds (I) or (II) containing nicotinic acid fragments and ester groups; wherein, the structural formula of compound f is: 、 or Among them, R3: 2-F, 2-Cl, 2-Br, 4-Cl, 6-F, 6-Cl, 6-Br, Or 2,6-diCl.

3. The method for preparing an N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group structure as described in claim 1, characterized in that, In step one, the organic solvent is dimethyl sulfoxide or glacial acetic acid, the molar ratio of compound a to 4-aminophenol, 2-methyl-4-aminophenol, 3-aminophenol or 2-methyl-5-aminophenol is 1:1, and the reaction temperature is 85-110℃.

4. The method for preparing an N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group structure as described in claim 1, characterized in that, In step two, the organic solvent is dichloromethane or tetrahydrofuran, the molar ratio of compound f to intermediate d or intermediate e is 1:1.1, the molar ratio of compound f to activating reagent 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:2, the molar ratio of compound f to catalyst 4-dimethylaminopyridine is 1:0.2, the reaction temperature is 25-45℃, and the eluent used for column chromatography is ethyl acetate-petroleum ether.

5. The application of the N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group as a protoporphyrinogen oxidase inhibitor according to claim 1.

6. The application of an N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group structure as described in claim 1 in the control of weeds.

7. The application according to claim 6, characterized in that, The weeds are either monocotyledonous or dicotyledonous.

8. The application according to any one of claims 6-7, characterized in that, It takes place in the presence of crops, such as wheat, corn, rice, cotton, soybeans, or peanuts.

9. The use of the N-phenylphthalimide compound containing a nicotinic acid fragment and an ester group as an active ingredient in the preparation of herbal remedies for removing impurities, as described in claim 1.

10. The application according to claim 9, characterized in that, The active ingredient in the drug is applied at a concentration of 75-300 g ai / ha.

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