HPPD inhibitor with morpholine cyclic carbonyl structure, composition and application

Abstract

The invention discloses an HPPD inhibitor with a morpholine cyclic carbonyl structure, a composition and application, and belongs to the field of herbicides. The HPPD inhibitor with the morpholine cyclic carbonyl structure, provided by the invention, has a relatively good control effect on broadleaf weeds and grassy weeds. The preferable compound still keeps super-efficient herbicidal activity on selected weeds at the extremely low concentration of 9.375 g ai / ha, is superior to that of a commercially available HPPD inhibition type herbicide mesotrione, and shows absolute advantages for a malignant weed brome in a wheat field. Meanwhile, the compound is high in crop safety, the preferable compound has no damage to wheat and peanuts under the dosage of 150 g ai / ha, the inhibition rate of the preferable compound to various crops is remarkably lower than that of mesotrione even under the high concentration of 600 g ai / ha, and the compound is a selective herbicide with excellent development potential.

Description

Technical Field

[0001] This invention relates to the field of herbicides, and more particularly to an HPPD inhibitor having a morpholine ring carbonyl structure, a composition thereof, and its application. Background Technology

[0002] Pesticides, as one of the most economical and effective means of ensuring food production, play a crucial role in mitigating huge economic losses. Among them, herbicides, as an important category of pesticides, are essential for controlling weeds in the field and ensuring crop yields through their rational use. 4-Hydroxyphenylpyruvate dioxygenase (HPPD), a novel herbicide target identified in the 1990s, possesses significant advantages such as high efficiency, low toxicity, environmental friendliness, and safety for subsequent crops. Of particular note is that, compared to the severe resistance problems faced by traditional herbicides such as acetate synthases (AHAs), acetyl-CoA carboxylases (ACCases), and photosystem II (PSII) inhibitors, HPPD-inhibiting herbicides have experienced extremely slow resistance development, with few reports of resistance to date. Furthermore, they exhibit no cross-resistance with other types of herbicides, demonstrating excellent control potential against resistant weeds and are considered a promising new generation of herbicides.

[0003] However, commercially available HPPD-inhibiting herbicides currently face significant limitations in practical applications. The vast majority are primarily suitable for weed control in cornfields, exhibiting poor selectivity for other major crops such as rice, wheat, rapeseed, soybeans, and peanuts, easily causing crop damage. This severely restricts the expansion of their application scope. Although researchers have successfully developed some novel HPPD inhibitors with high safety for specific crops in recent years through molecular design and structural optimization—for example, the HPPD inhibitor provided by CN112300092B exhibits good herbicidal activity while showing high safety for peanuts—overall, highly selective HPPD-inhibiting herbicides suitable for major crops such as wheat and rice remain extremely scarce. Summary of the Invention

[0004] Purpose of the invention: The purpose of this invention is to provide an HPPD inhibitor with a morpholine ring carbonyl structure that optimizes herbicidal activity and improves crop safety; the second purpose is to provide a composition containing the HPPD inhibitor and its application.

[0005] Technical solution: The HPPD inhibitor of the present invention has a morpholine ring carbonyl structure as shown in formula (I): Where R is selected from , Any of the following, R 1 Selected from , , , , Any of the following, R 2 Selected from hydrogen or .

[0006] Preferably, the HPPD inhibitor has a structure as shown in any one of formulas (A1)-(A8) and (B1)-(B8): , , , , , , , , , , , , , , , .

[0007] The composition of the present invention contains an HPPD inhibitor having a morpholine ring carbonyl structure as described above, or its stereoisomers, tautomers, or salts.

[0008] Preferably, the composition further comprises one or more additional components selected from surfactants, solid diluents, liquid diluents, buffers, defoamers, thickeners, antifreeze agents, antimicrobial agents, and film-forming agents.

[0009] The application of the HPPD inhibitor or composition having a morpholine ring carbonyl structure described in this invention in crop cultivation.

[0010] Preferably, the application is used for weed control in crop cultivation.

[0011] Preferably, the crop is wheat, peanut, or corn.

[0012] Preferably, the weeds are broadleaf weeds and / or grass weeds.

[0013] Preferably, the broadleaf weeds are any one or more of Abutilon theophrasti, Zinnia elegans, and Portulaca oleracea, and the grass weeds are any one or more of Barnyardgrass and Bromus spp.

[0014] Preferably, the application concentration of the HPPD inhibitor having a morpholine ring carbonyl structure in the application is not less than 9.375 g ai / ha.

[0015] Beneficial Effects: Compared with the prior art, the present invention has the following significant advantages: 1. The HPPD inhibitor with morpholine ring carbonyl structure has good control effect on both broadleaf and grass weeds; 2. The preferred compound maintains ultra-high efficiency herbicidal activity against selected weeds at an extremely low concentration of 9.375 g ai / ha, which is superior to the commercially available HPPD-inhibiting herbicide mesotrione, and shows an absolute advantage against the noxious weed brome in wheat fields; 3. The HPPD inhibitor with morpholine ring carbonyl structure has high crop safety. At a dose of 150 g ai / ha, the preferred compound does not cause any damage to wheat and peanuts. Even at a high concentration of 600 g ai / ha, the inhibition rate of the preferred compound against various crops is significantly lower than that of mesotrione, making it a selective herbicide with excellent development potential. Detailed Implementation

[0016] The technical solution of the present invention will be further described below.

[0017] All reagents used in the synthesis of this invention are commercially available and can be used without further purification. A Varian Mercury-Plus nuclear magnetic resonance spectrometer (400 MHz) was used with deuterated chloroform (CDCl3) as solvent and tetramethylsilane (TMS) as internal standard to determine the compounds. 1 1H NMR spectrum. Chemical shift ( δ (Using the triplet center of CDCl3 (77.0 ppm) as a reference)

[0018] Example 1: Synthesis of compound (A1) 2-(2,4-dichloro-3-(morpholin-4-carbonyl)benzoyl)-3-hydroxycyclohexyl-2-en-1-one

[0019]

[0020] The synthetic route for compound (A1) is as follows:

[0021] The specific synthesis steps are as follows:

[0022] (1) Intermediate 2,6-dichlorobenzoyl chloride (A 1-2 Synthesis of )

[0023] Add 30 g (157.06 mmol) of 2,6-dichlorobenzoic acid and 150 mL of ultra-dry dichloromethane to a single-necked flask, then slowly add 26.58 mL (314.12 mmol) of oxaloyl chloride at 0°C, followed by 1 mL of [unspecified substance]. N,N The reaction was catalyzed by dimethylformamide, followed by a 3-hour recovery to room temperature. After the reaction was complete, the solvent was removed using a rotary evaporator to obtain 26.3 g of the intermediate 2,6-dichlorobenzoyl chloride (A).1-2 ), with a yield of 80%.

[0024] (2) Intermediate (2,6-dichlorophenyl)(morpholino) methyl ketone (A) 1-3 Synthesis of )

[0025] Add 150 mL of ultra-dry dichloromethane, 12.04 mL (138.22 mmol) of morpholine, and 34.9 mL (251.32 mmol) of triethylamine to a single-necked flask. Then, slowly add 26.32 g (125.66 mmol) of compound A at 0°C. 1-2 The mixture was reacted with a dichloromethane solution and then allowed to return to room temperature for 3 h. After the reaction was complete, 100 mL of saturated sodium bicarbonate aqueous solution was added to the system, and the aqueous phase was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. Column chromatography was performed using a 2:1 (v / v) petroleum ether-ethyl acetate mixture as the eluent to obtain 33 g of the intermediate (2,6-dichlorophenyl)(morpholino) methyl ketone (A). 1-3 ), with a yield of 91%.

[0026] (3) Intermediate (2,6-dichloro-3-iodophenyl)(morpholino) methyl ketone (A) 1-4 Synthesis of )

[0027] Add compound A to a single-necked flask 1-3 30 g (115.33 mmol) of trifluoromethanesulfonic acid (14.06 g (104.85 mmol)) was slowly added at 0°C, followed by multiple small additions at 0°C. N -Iodosuccinimide 32.04 g (185.23 mmol) was reacted at 0 °C for 4 h. After the reaction was complete, the reaction system was added dropwise to 100 mL of ice water, followed by extraction of the aqueous phase three times with 80 mL of dichloromethane, washing three times with 10% sodium thiosulfate solution, and washing once with saturated sodium chloride. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain 36.3 g of the intermediate (2,6-dichloro-3-iodophenyl)(morpholino) methyl ketone (A). 1-4 ), with a yield of 90%.

[0028] (4) Intermediate 2,4-dichloro-3-(morpholino-4-carbonyl)benzonitrile (A) 1-5 Synthesis of )

[0029] Add compound A to a single-necked flask 1-5 4.0 g (10.36 mmol) and 1.86 g (20.72 mmol) of cuprous cyanide were added under a nitrogen atmosphere. N,N 50 mL of dimethylformamide was added, and the mixture was then heated to 155 °C and refluxed overnight. After the reaction was complete, the mixture was dried in a 90 °C water bath. N,N -Dimethylformamide was separated by column chromatography using petroleum ether-ethyl acetate (v / v) as the eluent. 1.66 g of the intermediate 2,4-dichloro-3-(morpholino-4-carbonyl)benzonitrile (A) was obtained. 1-5 ), with a yield of 56%.

[0030] (5) Intermediate 2,4-dichloro-3-(morpholino-4-carbonyl)benzoic acid (A) 1-6 Synthesis of )

[0031] Add compound A to a single-necked flask 1-5 1.66 g (5.82 mmol), 3.27 g (58.22 mmol) potassium hydroxide, 5 mL methanol, and 15 mL ethanol were added dropwise with 30% hydrogen peroxide solution at 0 °C, followed by slow heating to 80 °C and reflux overnight. After the reaction, the solvent was removed using a rotary evaporator, and the mixture was separated by adding 30 mL water and 30 mL ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The aqueous phase was adjusted to pH 4.5 ± 0.5 with hydrochloric acid, and then extracted five times with dichloromethane to obtain the organic phase. The organic phase was dried overnight with anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. The organic phase was then dried at 50 °C to obtain 1.30 g of the intermediate 2,4-dichloro-3-(morpholino-4-carbonyl)benzoic acid (A). 1-6 ), with a yield of 73%.

[0032] (6) Intermediate 2,4-dichloro-3-(morpholino-4-carbonyl)benzoyl chloride (A 1-7 Synthesis of )

[0033] Add compound A to a single-necked flask 1-6 1.0 g (3.29 mmol) of ultra-dry dichloromethane (35 mL) was slowly added at 0°C along with 0.56 mL (6.58 mmol) of oxalyl chloride and 0.2 mL of other oxalyl chloride. N,N The reaction was catalyzed by dimethylformamide, followed by a 3-hour recovery to room temperature. After the reaction was complete, the solvent was removed by rotary evaporation to give 1 g of the intermediate 2,4-dichloro-3-(morpholino-4-carbonyl)benzoyl chloride (A). 1-7 ), with a yield of 80%.

[0034] (7) Intermediate 2,4-dichloro-3-(morpholino-4-carbonyl)benzoic acid-3-oxocyclohexyl-1-en-1-yl ester (A) 1-8 Synthesis of )

[0035] Add 325 mg (2.90 mmol) of 1,3-cyclohexanedione and 40 mL of ultra-dry dichloromethane to a single-necked flask, stir at room temperature until the solid dissolves, add 0.73 mL (5.27 mmol) of triethylamine at 0°C, and then add 850 mg (2.64 mmol) of compound A.1-7 The reaction was carried out in a dichloromethane solution at room temperature for 4 h. After the reaction was complete, a saturated sodium bicarbonate solution was added to the system, and the aqueous phase was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. Column chromatography was performed using a 2:1 (v / v) petroleum ether-ethyl acetate mixture as the eluent to obtain 450 mg of the intermediate 2,4-dichloro-3-(morpholino-4-carbonyl)benzoic acid-3-oxocyclohexyl-1-en-1-yl ester (A). 1-8 ), with a yield of 37%.

[0036] (8) Synthesis of 2-(2,4-dichloro-3-(morpholin-4-carbonyl)benzoyl)-3-hydroxycyclohex-2-en-1-one (A1)

[0037] Add compound A to a single-necked flask 1-8 250 mg (0.63 mmol), 30 mL acetonitrile, 0.17 mL triethylamine, and 0.25 mL trimethylcyanosilane were stirred overnight at room temperature. After the reaction was complete, acetic acid was added to adjust the pH to 5. The solvent was removed by rotary evaporation. 30 mL water / 30 mL dichloromethane was added for separation. The aqueous phase was extracted three times with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation. Column chromatography was performed using a 10:1 (v / v) dichloromethane-methanol mixture to give 90 mg of the target compound 2-(2,4-dichloro-3-(morpholino-4-carbonyl)benzoyl)-3-hydroxycyclohexyl-2-en-1-one (A1), with a yield of 20%. The characterization data are as follows: MS (ES-API, pos. ion) m / z: 398.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 16.82 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 3.84 (d, J = 5.2 Hz, 2H), 3.79 (d, J = 4.3 Hz, 2H), 3.69 (d, J = 3.5 Hz,2H), 3.35 – 3.31 (m, 2H), 2.79 (dd, J = 10.9, 6.0 Hz, 2H), 2.46 – 2.37 (m, 2H), 2.04 (dd, J = 13.3, 6.9 Hz, 2H).

[0038] Example 2: Synthesis of compound (A2) 2-(2,4-dichloro-3-(morpholin-4-carbonyl)benzoyl)-3-hydroxy-5-methylcyclohexyl-2-en-1-one

[0039]

[0040] The specific synthesis steps are as described in Example 1. In step 7, 365.28 mg (2.90 mmol) of 5-methylcyclohexane-1,3-dione was used to replace 1,3-cyclohexanedione, while the other steps remained unchanged. This yielded 327 mg of the target compound 2-(2,4-dichloro-3-(morpholino-4-carbonyl)benzoyl)-3-hydroxy-5-methylcyclohex-2-en-1-one (A2) in 30% yield. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 412.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 16.81 (s,1H), 7.37 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 3.74 (s, 2H), 3.64 (s,4H), 2.78 (dd, J = 18.2, 2.9 Hz, 1H), 2.58 – 2.45 (m, 6H), 1.14 (d, J = 6.4 Hz, 3H).

[0041] Example 3: Compound of formula (A3) (2,6-dichloro-3-(5-hydroxy-1-methyl-1 ... H Synthesis of pyrazole-4-carbonyl)phenyl)(morpholino)methyl ketone

[0042]

[0043] For specific synthesis steps, please refer to Example 1. In step 7, 1-methyl-1 H 284.37 mg (2.90 mmol) of pyrazole-5-ol was replaced with 1,3-cyclohexanedione, with the remaining steps unchanged, to finally obtain 212 mg of the target compound (2,6-dichloro-3-(5-hydroxy-1-methyl-1-yl)). H (-pyrazole-4-carbonyl)phenyl)(morpholino)methyl ketone (A3), yield 21%. Characterization data are as follows: MS (ES-API, pos. ion) m / z: 384.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 3.82 (s, 3H), 3.72 (m, 2H), 2.74(d, J = 10.8 Hz, 2H), 2.28 (m, 4H).

[0044] Example 4: Compound of formula (A4) (2,6-dichloro-3-(5-hydroxy-1,3-dimethyl-1 ... H Synthesis of pyrazole-4-carbonyl)phenyl)(morpholino)methyl ketone

[0045]

[0046] For specific synthesis steps, please refer to Example 1. In step 7, 1,3-dimethyl-1 H 325.03 mg (2.90 mmol) of pyrazole-5-ol was replaced with 1,3-cyclohexanedione, with the remaining steps unchanged, to finally obtain 273 mg of the target compound (2,6-dichloro-3-(5-hydroxy-1,3-dimethyl-1-yl)-pyrazole-5-ol). H -pyrazole-4-carbonyl)phenyl)(morpholino)methyl ketone (A4), yield 26%. Characterization data are as follows: MS (ES-API, pos. ion) m / z: 398.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 3.78 (s, 3H), 3.66 (m, 2H), 3.48 (m,3H), 2.72 (d, J = 10.8 Hz, 2H), 2.28 (m, 4H).

[0047] Example 5: Compound of formula (A5) (3-cyclopropyl-5-hydroxy-1-methyl-1-yl) H Synthesis of pyrazol-4-yl)(2,4-dichloro-3-(morpholin-4-carbonyl)phenyl) ketone

[0048]

[0049] For specific synthesis steps, refer to Example 1. In step 7, 3-cyclopropyl-1-methyl-1 H400.50 mg (2.90 mmol) of pyrazole-5-ol was replaced with 1,3-cyclohexanedione, with the remaining steps unchanged, to finally obtain 179.2 mg of the target compound (3-cyclopropyl-5-hydroxy-1-methyl-1-yl-2 ... H -pyrazol-4-yl)(2,4-dichloro-3-(morpholin-4-carbonyl)phenyl)methyl ketone (A5), yield 16%. Characterization data are as follows: MS (ES-API, pos. ion) m / z: 424.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.38 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 3.78 (s, 2H), 3.68 – 3.64 (m, 2H), 3.54 (s, 3H), 2.62 – 2.54 (m, 4H), 0.96 (d, J = 4.8 Hz,1H), 0.76 (s, 2H), 0.38 (d, J = 7.6 Hz, 2H).

[0050] Example 6: Compound of formula (A6) 2-((4-(2,4-dichloro-3-(morpholin-4-carbonyl)benzoyl)-1-methyl-1 H Synthesis of pyrazol-5-yl)oxy)-1-phenylethyl-1-one

[0051]

[0052] Compound A3300 mg (0.78 mmol) was added to a single-necked flask. N,N 20 mL of dimethylformamide and 161.8 mg (1.17 mmol) of potassium carbonate were stirred at room temperature for 10 min until completely dissolved. Then, 171 mg (0.859 mmol) of benzoylmethyl bromide was added, and the reaction was carried out at room temperature for 4 h. After the reaction was complete, the reaction mixture was quenched with 2 mL of water, extracted three times with 50 mL of ethyl acetate, and the organic phases were combined. The mixture was washed once with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. Column chromatography was performed using a 3:1 (v / v) petroleum ether-ethyl acetate mixture as the eluent to obtain 176 mg of the target compound 2-((4-(2,4-dichloro-3-(morpholino-4-carbonyl)benzoyl)-1-methyl-1- H-pyrazol-5-yl)oxy)-1-phenylethyl-1-one (A6), yield 45%. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 502.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.4 Hz, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.58 (t, J =7.8 Hz, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.2Hz, 1H), 5.88 (s, 2H), 3.86 (s, 3H), 3.78 (s, 2H), 3.66 (s, 2H), 2.58 (s, 4H).

[0053] Example 7: Compound of formula (A7) 2-((4-(2,4-dichloro-3-(morpholin-4-carbonyl)benzoyl)-1,3-dimethyl-1 H Synthesis of pyrazol-5-yl)oxy)-1-phenylethyl-1-one

[0054]

[0055] Compound A4 300 mg (0.753 mmol) was added to a single-necked flask. N,N 20 mL of dimethylformamide and 156.2 mg (1.13 mmol) of potassium carbonate were stirred at room temperature for 10 min until completely dissolved. Then, 164.9 mg (0.829 mmol) of benzoylmethyl bromide was added, and the reaction was continued at room temperature for 4 h. After the reaction was complete, the reaction mixture was quenched with 2 mL of water, extracted three times with 50 mL of ethyl acetate, and the organic phases were combined. The mixture was washed once with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. Column chromatography was performed using a 3:1 (v / v) petroleum ether-ethyl acetate mixture as the eluent to obtain 202 mg of the target compound 2-((4-(2,4-dichloro-3-(morpholino-4-carbonyl)benzoyl)-1,3-dimethyl-1 H -pyrazol-5-yl)oxy)-1-phenylethyl-1-one (A7), yield 52%. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 516.1 [M+H] + .1 HNMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.4 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.48(t, J = 7.7 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 5.88 (s, 2H), 3.86 (s, 3H), 3.76 (s, 2H), 3.64 (s, 2H), 3.52 (m, 3H), 2.58 (s, 4H).

[0056] Example 8: Compound of formula (A8) 2-((3-cyclopropyl-4-(2,4-dichloro-3-(morpholin-4-carbonyl)benzoyl)-1-methyl-1 H Synthesis of pyrazol-5-yl)oxy)-1-phenylethyl-1-one

[0057]

[0058] Compound A5300 mg (0.707 mmol) was added to a single-necked flask. N,N 20 mL of dimethylformamide and 146.58 mg (1.06 mmol) of potassium carbonate were stirred at room temperature for 10 min until completely dissolved. Then, 154.82 mg (0.778 mmol) of benzoylmethyl bromide was added, and the mixture was reacted at room temperature for 4 h. After the reaction was complete, the reaction mixture was quenched with 2 mL of water, extracted three times with 50 mL of ethyl acetate, and the organic phases were combined. The mixture was washed once with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. Column chromatography was performed using a 3:1 (v / v) petroleum ether-ethyl acetate mixture as the eluent to obtain 145.7 mg of the target compound 2-((3-cyclopropyl-4-(2,4-dichloro-3-(morpholino-4-carbonyl)benzoyl)-1-methyl-1 H -pyrazol-5-yl)oxy)-1-phenylethyl-1-one (A8), yield 38%. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 542.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.4 Hz, 2H), 7.66 (t, J= 7.4Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.2 Hz,1H), 5.88 (s, 2H), 3.84 (s, 3H), 3.78 (s, 2H), 3.66 (s, 2H), 2.56 (s, 4H),1.10 – 1.04 (m, 1H), 0.78 – 0.74 (m, 2H), 0.46 – 0.38 (m, 2H).

[0059] Example 9: Synthesis of compound (B1) 2-(2,4-dichloro-3-(2,6-dimethylmorpholino-4-carbonyl)benzoyl)-3-hydroxycyclohexyl-2-en-1-one

[0060]

[0061] The specific synthetic steps are as described in Example 1. In step 2, morpholine was replaced with 17.03 mL (138.22 mmol) of 2,6-dimethylmorpholine, while the other steps remained unchanged. The final yield was 31.86 g of the target compound 2-(2,4-dichloro-3-(2,6-dimethylmorpholine-4-carbonyl)benzoyl)-3-hydroxycyclohexyl-2-en-1-one (B1), with a yield of 88%. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 426.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 16.86 (s, 1H), 7.40(d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 3.72 (d, J = 49.6 Hz, 4H), 2.88 –2.76 (m, 2H), 2.48 (t, J = 6.2 Hz, 2H), 2.06 – 1.98 (m, 4H), 1.16 (d, J = 6.4 Hz, 6H).

[0062] Example 10: Synthesis of compound (B2) 2-(2,4-dichloro-3-(2,6-dimethylmorpholin-4-carbonyl)benzoyl)-3-hydroxycyclohexyl-2-en-1-one

[0063]

[0064] The specific synthesis steps are as described in Example 9. In step 7, 366.10 g (2.90 mmol) of 5-methylcyclohexane-1,3-dione was used to replace 1,3-cyclohexanedione, while the other steps remained unchanged. This yielded 440.8 mg of the target compound 2-(2,4-dichloro-3-(2,6-dimethylmorpholino-4-carbonyl)benzoyl)-3-hydroxycyclohex-2-en-1-one (B2) in 38% yield. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 440.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 16.86(s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 3.74 (s, 2H), 2.84(d, J = 17.4 Hz, 1H), 2.76 (d, J = 10.8 Hz, 2H), 2.58 – 2.46 (m, 2H), 2.36 (ddd, J = 14.8, 10.6, 5.4 Hz, 1H), 2.22 – 2.12 (m, 1H), 1.98 (t, J = 10.6 Hz, 2H), 1.16(t, J = 5.8 Hz, 9H).

[0065] Example 11: Compound of formula (B3) (2,4-dichloro-3-(2,6-dimethylmorpholino-4-carbonyl)phenyl)(5-hydroxy-1-methyl-1 H Synthesis of pyrazol-4-yl)methyl ketone

[0066]

[0067] For specific synthesis steps, please refer to Example 9. In step 7, 1-methyl-1 H 284.37 mg (2.90 mmol) of pyrazole-5-ol was replaced with 1,3-cyclohexanedione, with the remaining steps unchanged, to finally obtain 348.8 mg of the target compound (2,4-dichloro-3-(2,6-dimethylmorpholino-4-carbonyl)phenyl)(5-hydroxy-1-methyl-1 H 3-Pyrazol-4-yl)methyl ketone (B3), yield 32%. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 412.1 [M+H]+ . 1 H NMR (400 MHz, CDCl3) δ7.52 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.24 (s, 1H), 3.78 (s, 3H), 3.68 – 3.58 (m, 2H), 2.72 (d, J = 10.6 Hz, 2H), 2.12 (t, J = 10.6 Hz, 2H), 1.18(d, J = 6.2 Hz, 6H).

[0068] Example 12: Compound of formula (B4) (2,4-dichloro-3-(2,6-dimethylmorpholino-4-carbonyl)phenyl)(5-hydroxy-1,3-dimethyl-1 H Synthesis of pyrazol-4-yl)methyl ketone

[0069]

[0070] For specific synthesis steps, please refer to Example 9. In step 7, 1,3-dimethyl-1 H 325.03 mg (2.90 mmol) of pyrazole-5-ol was replaced with 1,3-cyclohexanedione, with the remaining steps unchanged, to finally obtain 403.2 mg of the target compound (2,4-dichloro-3-(2,6-dimethylmorpholine-4-carbonyl)phenyl)(5-hydroxy-1,3-dimethyl-1 H 3-Pyrazol-4-yl)methyl ketone (B4), yield 36%. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 426.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 3.82 (s, 3H), 3.64(s, 5H), 2.70 (d, J = 10.8 Hz, 2H), 1.28 (s, 2H), 1.18 (d, J = 5.6 Hz, 6H).

[0071] Example 13: Compound of formula (B5) (3-cyclopropyl-5-hydroxy-1-methyl-1-yl) HSynthesis of pyrazol-4-yl)(2,4-dichloro-3-(2,6-dimethylmorpholin-4-carbonyl)phenyl) ketone

[0072]

[0073] For specific synthesis steps, please refer to Example 9. In step 7, 3-cyclopropyl-1-methyl-1 H 400.50 mg (2.90 mmol) of pyrazole-5-ol was replaced with 1,3-cyclohexanedione, with the remaining steps unchanged, to finally obtain 249.9 mg of the target compound (3-cyclopropyl-5-hydroxy-1-methyl-1-yl-2 ... H -pyrazol-4-yl)(2,4-dichloro-3-(2,6-dimethylmorpholino-4-carbonyl)phenyl) methyl ketone (B5), yield 21%. Characterization data are as follows: MS (ES-API, pos. ion) m / z: 452.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 3.78 (s,2H), 3.64 (s, 3H), 2.68 (d, J = 10.8 Hz, 2H), 2.04 (t, J = 10.6 Hz, 2H), 1.16 (d, J = 6.2 Hz, 6H), 1.08 (td, J = 8.2, 4.2 Hz, 1H), 0.78 (d, J = 4.2 Hz, 2H), 0.48(d, J = 7.4 Hz, 2H).

[0074] Example 14: Compound of formula (B6) 2-((4-(2,4-dichloro-3-(2,6-dimethylmorpholino-4-carbonyl)benzoyl)-1-methyl-1 H Synthesis of pyrazol-5-yl)oxy)-1-phenylethyl-1-one

[0075]

[0076] Compound B3 300 mg (0.694 mmol) was added to a single-necked flask. N,N20 mL of dimethylformamide and 144.91 mg (1.04 mmol) of potassium carbonate were stirred at room temperature for 10 min until completely dissolved. Then, 151.95 mg (0.763 mmol) of benzoylmethyl bromide was added, and the mixture was reacted at room temperature for 4 h. After the reaction was complete, the reaction mixture was quenched with 2 mL of water, extracted three times with 50 mL of ethyl acetate, and the organic phases were combined. The mixture was washed once with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. Column chromatography was performed using a 3:1 (v / v) petroleum ether-ethyl acetate mixture as the eluent to obtain 169.32 mg of the target compound 2-((4-(2,4-dichloro-3-(2,6-dimethylmorpholino-4-carbonyl)benzoyl)-1-methyl-1 H -pyrazol-5-yl)oxy)-1-phenylethyl-1-one (B6), yield 46%. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 530.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.4 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 5.42 (s, 2H), 3.84 (s, 3H), 3.74 (s, 2H), 2.58 – 2.46(m, 4H). 1.16 (d, J = 6.4 Hz, 6H).

[0077] Example 15: Compound of formula (B7) 2-((4-(2,4-dichloro-3-(2,6-dimethylmorpholin-4-carbonyl)benzoyl)-1,3-dimethyl-1 H Synthesis of pyrazol-5-yl)oxy)-1-phenylethyl-1-one

[0078]

[0079] Compound B4 300 mg (0.704 mmol) was added to a single-necked flask. N,N20 mL of dimethylformamide and 146.95 mg (1.06 mmol) of potassium carbonate were stirred at room temperature for 10 min until completely dissolved. Then, 154.08 mg (0.774 mmol) of benzoylmethyl bromide was added, and the mixture was reacted at room temperature for 4 h. After the reaction was complete, the reaction mixture was quenched with 2 mL of water, extracted three times with 50 mL of ethyl acetate, and the organic phases were combined. The mixture was washed once with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. Column chromatography was performed using a 3:1 (v / v) petroleum ether-ethyl acetate mixture as the eluent to obtain 145.59 mg of the target compound 2-((4-(2,4-dichloro-3-(2,6-dimethylmorpholino-4-carbonyl)benzoyl)-1,3-dimethyl-1 H -pyrazol-5-yl)oxy)-1-phenylethyl-1-one (B7), yield 38%. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 544.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.4Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.2 Hz,1H), 5.86 (s, 2H), 3.78 (s, 3H), 3.66 (s, 2H), 3.58 (m, 3H), 2.36 – 2.28 (m,4H). 1.15 (d, J = 6.4 Hz, 6H).

[0080] Example 16: Compound of formula (B8) 2-((3-cyclopropyl-4-(2,4-dichloro-3-(2,6-dimethylmorpholin-4-carbonyl)benzoyl)-1-methyl-1 H Synthesis of pyrazol-5-yl)oxy)-1-phenylethyl-1-one

[0081]

[0082] Compound B5 300 mg (0.663 mmol) was added to a single-necked flask. N,N20 mL of dimethylformamide and 138.49 mg (0.995 mmol) of potassium carbonate were stirred at room temperature for 10 min until completely dissolved. Then, 145.22 mg (0.729 mmol) of benzoylmethyl bromide was added, and the reaction was carried out at room temperature for 4 h. After the reaction was complete, the reaction mixture was quenched with 2 mL of water, extracted three times with 50 mL of ethyl acetate, and the organic phases were combined. The mixture was washed once with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. Column chromatography was performed using a 3:1 (v / v) petroleum ether-ethyl acetate mixture as the eluent to obtain 121.07 mg of the target compound 2-((3-cyclopropyl-4-(2,4-dichloro-3-(2,6-dimethylmorpholino-4-carbonyl)benzoyl)-1-methyl-1 H -pyrazol-5-yl)oxy)-1-phenylethyl-1-one (B8), yield 32%. Its characterization data are as follows: MS (ES-API, pos. ion) m / z: 570.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.4 Hz, 2H), 7.66 (t, J =7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.2Hz, 1H), 5.88 (s, 2H), 3.84 (s, 3H), 3.56 – 3.52 (m, 2H), 2.66 (d, J = 10.8 Hz, 2H), 1.98 (t, J = 10.6 Hz, 2H), 1.64 (s, 1H), 1.16 (d, J = 6.4 Hz, 6H), 0.76 –0.72 (m, 2H), 0.38 (dd, J = 8.2, 2.1 Hz, 2H).

[0083] Experimental Example 1: Herbicidal Activity Assay

[0084] The post-emergence herbicidal activity of the HPPD inhibitors obtained in Examples 1-16 against *Abutilon theophrasti*, *Zinnia elegans*, *Portulaca oleracea*, *Barnyardgrass*, and *Brassica rapa* was determined. The commercially available herbicide mesotrione was used as a positive control. All tested compounds were... N,N - Dimethylformamide (DMF) as solvent, Tween 80 as emulsifier (VDMF V Tween 80 A 200 g / L emulsifiable concentrate was prepared by mixing a 99:1 ratio of active ingredients with water; this concentrate was then diluted with water to the desired concentration and used to treat potted plants in a greenhouse. The soil used in the experiment was clay with a pH of 6.5, an organic matter content of 1.8%, a cation exchange capacity (CEC) of 12.1 mol / kg, and a clay content of 38%. The dosage of the formulation (g ai / ha) was calculated by dividing the total mass of the active ingredients in the formulation by the surface area of ​​the flowerpot.

[0085] Fill 10 cm diameter plastic pots with soil to a depth of 9 cm, and sow 25 seeds of the test weeds (velvetleaf, zinnia, purslane, barnyard grass, or wild oats) in each pot at a depth of 2 cm. Place the pots in a greenhouse at 25℃ and 50% relative humidity for cultivation. After the weeds emerge, use an automatic sprayer (manufactured by Changshu Jianyuan Landscape Engineering Co., Ltd.) to spray the diluted formulation at a rate of 30 mL / m². 2 The spray volume is evenly applied to the stems of the weeds.

[0086] Dicotyledonous weeds were treated at the 2-leaf stage, and monocotyledonous weeds at the 1-leaf stage. Post-emergence application dosages included six concentration gradients: 300, 150, 75, 37.5, 18.75, and 9.375 g ai / ha. The solvent control group (Tween 80+DMF) was sprayed using the same solvent-emulsifier (V) as the tested compound formulation. DMF V Tween 80 =99:1), at 30 mL / m 2 The spray volume was uniform, ensuring that the total solvent spray volume was completely consistent with that of each tested compound treatment group. Untreated seedlings served as a blank control, while the solvent control group was sprayed with only the solvent (Tween 80 + DMF). Twenty-one days after treatment, the herbicidal activity was visually evaluated using a 0-100 grading system.

[0087] The herbicidal activity of the HPPD inhibitors obtained in Examples 1-16 at concentrations of 300 and 150 g ai / ha is shown in Table 1 below.

[0088] Table 1. Post-emergence herbicidal activity (%) of the HPPD inhibitors obtained in Examples 1-16

[0089]

[0090] The herbicidal activity of the HPPD inhibitors obtained in some examples at concentrations of 75 and 37.5 g ai / ha is shown in Table 2 below.

[0091] Table 2. Post-emergence herbicidal activity (%) of the HPPD inhibitors obtained in the examples against weeds at concentrations of 75 and 37.5 g ai / ha.

[0092]

[0093] The herbicidal activity of the HPPD inhibitors obtained in some examples at concentrations of 18.75 and 9.375 g ai / ha is shown in Table 3 below.

[0094] Table 3. Post-emergence herbicidal activity (%) of the HPPD inhibitors obtained in the examples against weeds at concentrations of 18.75 and 9.375 g ai / ha.

[0095]

[0096] The results in Tables 1-3 show that compounds A1-A8 and B1-B8, which have morpholine ring carbonyl structures and were synthesized in Examples 1-16, exhibit good control effects against both broadleaf weeds such as velvetleaf, zinnia, and purslane, and grass weeds such as barnyard grass and bromegrass. At extremely low concentrations of 18.75 and 9.375 g ai / ha, compounds A1, A2, and B1 maintained highly efficient herbicidal activity against broadleaf weeds such as velvetleaf, zinnia, and purslane, comparable to the commercial herbicide mesotrione. Furthermore, against the noxious weed bromegrass in wheat fields, compounds A1, A2, and B1 showed an absolute advantage over mesotrione, exhibiting higher herbicidal activity.

[0097] Experimental Example 2: Crop Safety Determination

[0098] Rice, wheat, corn, peanuts, rapeseed, and soybeans were planted in 10 cm diameter pots filled with experimental soil and cultivated in a greenhouse at 25°C and 50% relative humidity. The commercial herbicide mesotrione was used as a control. When the crops reached the 4-leaf stage, they were sprayed using the method described in Experiment 1 at doses of 150, 300, and 600 g ai / ha, respectively. Visual damage symptoms and growth status of individual plants were observed regularly. After 21 days of treatment, visual evaluation was performed using a 0-100 grading system.

[0099] literature Pestic.Biochem.Physiol Patents CN112300092B and 2025, 215, 106692 report the design, synthesis, and herbicidal activity studies of a series of 2,4-dichlorobenzene-3-morpholine derivative HPPD inhibitors. However, these compounds have poor safety profiles for wheat, as shown in Table 4 below, failing to meet the practical needs of major crops in my country's agricultural production.

[0100] Table 4. Inhibition rates (%) of crops in Examples 1, 20, and 28 of CN112300092B.

[0101]

[0102] To assess the crop safety of A1, A2, and B1, crop selectivity tests were conducted at doses of 150, 300, and 600 g ai / ha in this embodiment. The results are shown in Table 5 below.

[0103] Table 5. Inhibition rates (%) of compounds A1, A2, and B1 in crops.

[0104]

[0105] The results showed that the sensitivity order of the six tested crops to compounds A1, A2, and B1 was: rapeseed > rice > soybean > corn > wheat ≈ peanut. Compared with the commercial herbicide mesotrione, compounds A1, A2, and B1 caused less damage to wheat and peanuts at the same dosage.

[0106] Most notably, compound A1 exhibits the highest safety profile among various crops, surpassing that of nicosulfuron: at a dose of 150 g ai / ha, compound A1 caused no damage to wheat or peanuts, while nicosulfuron caused 25% damage to wheat and 15% damage to peanuts; furthermore, even at a concentration of 600 g ai / ha, compound A1 maintained a high level of safety for wheat and peanuts.

[0107] In summary, the HPPD inhibitors with morpholine ring carbonyl structures obtained in Examples 1-16 not only have excellent herbicidal activity but also high crop safety, making them selective herbicides with great development potential.

Claims

1. A HPPD inhibitor having a morpholino ring carbonyl structure having a structure represented by formula (I): ###0001### (I) said HPPD inhibitor having a structure represented by any one of formula (Al) - formula (A8), formula (Bl) - formula (B8): ###0002### (Al) (A2) (A3) (A4) (A5) (A6) (A7) (A8) ###0003### (Bl) (B2) (B3) (B4) (B5) (B6) (B7) (B8) ， wherein, R is selected from any one of , R is selected from any one of 1 , , , , R is selected from any one of 2 .​​ 2. The HPPD inhibitor having a morpholine ring carbonyl structure according to claim 1, characterized by, said HPPD inhibitor having a morpholino ring carbonyl structure according to claim 1 or 2, or a stereoisomer, a tautomer, a salt thereof. 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. A composition characterized in that, said herbicide composition further containing any one or more of additional components of a surfactant, a solid diluent, a liquid diluent, a buffer, an antifoaming agent, a thickening agent, an antifreezing agent, an antimicrobial agent, a film forming agent.

4. The composition of claim 3, wherein, 5. Use of the HPPD inhibitor having a morpholino ring carbonyl structure according to claim 1 or 2, or the composition according to claim 3 or 4, in the cultivation of a crop plant. said use is a use in the control of weeds in the cultivation of a crop plant.

6. Use according to claim 5, characterized in that, said crop plant is wheat, peanut or corn.

7. Use according to claim 6, characterized in that, said weeds are broadleaf weeds and / or grass weeds.

8. Use according to claim 6, characterized in that, said broadleaf weeds are any one or more of Abutilon theophrasti, Zinnia elegans, Portulaca oleracea, and said grass weeds are any one or more of Echinochloa crus-galli, Bromus tectorum.

9. Use according to claim 8, characterized in that, said HPPD inhibitor having a morpholino ring carbonyl structure is applied at a concentration of not less than 9.375 g ai / ha.

10. Use according to any one of claims 5 to 9, characterized in that, ​

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