A benzene ring alkoxy-substituted sulfonylurea compound and its use in the preparation of a selective herbicide

Abstract

The present application relates to a kind of benzene ring alkoxy substitution sulfonylurea compound and its purposes in preparation herbicide.The compound of the present application has good prevention and removal effect on barnyard grass, elephant's ear grass, green bristlegrass, Japanese green bristlegrass, crabgrass, rape and amaranthus in 1 g / m2 dosage, soil treatment or stem-leaf treatment, and has good crop safety to wheat and rice in 2 g / m2 dosage, stem-leaf treatment or soil treatment.The compound can be used as selective herbicide in wheat field and rice field, and can also be used as herbicide in non-crop field such as forest or wasteland.The chemical structural formula of the benzene ring alkoxy substitution sulfonylurea compound is as follows:

Description

Technical Field

[0001] This invention belongs to the field of agricultural chemicals technology and relates to a class of phenylcycloalkoxysubstituted sulfonylurea compounds and their use in the preparation of selective herbicides, particularly their use in the preparation of herbicides safe for wheat and rice to control noxious grass weeds such as barnyardgrass, Japanese barnyardgrass, and sedge. Technical Background

[0002] Acetolactate synthase (AHAS, EC2.2.1.6) is a key enzyme catalyzing the biosynthesis of three branched-chain amino acids, including leucine (McCourt JA, et al. Amino Acids, 2006, 31(2), 173-210). This enzyme exists only in plants and microorganisms, therefore herbicides with this mechanism of action have high biocompatibility with mammals. Commercially available herbicides targeting AHAS mainly fall into five categories: sulfonylureas, imidazolinones, triazolidinediazoles, pyrimidine salicylates, and sulfonamide carbonyl triazolidinediazoles. AHAS-targeting herbicides effectively control weeds in farmland, playing a significant role in ensuring food security and promoting increased yields.

[0003] Since the beginning of the 21st century, significant progress has been made in the study of the crystal structure of AHAS-herbicide complexes, greatly deepening the understanding of the ultra-efficient herbicidal mechanism of AHAS inhibitors and providing new ideas for the further design and discovery of highly active compounds with different structures (Wang JG, et al. FEBS J., 2009, 276(5), 1282-1290; Garcia MD, et al. FEBS J., 2017, 284(13), 2037-2051; Garcia MD, et al. PNAS, 2017, 114(7), E1091-E1100; Lonhienne T, et al. PNAS, 2018, 115(9), E1945-E1954; Lonhienne T, et al. Nature, 2020, 586(7828), 317-321 ... al. Nat. Comm. 2022, 13(1), 3368).

[0004] Watching the wheatgrass ( Alopecurus aequalis Sobol. is an annual or biennial grass weed with strong seed reproduction ability, wide range of suitable habitats and easy spread. It is one of the top ten pests in Chinese farmland. In wheat fields, the roots of this grass can produce very strong allelochemicals that affect the growth of wheat roots and cause serious damage, which can lead to a significant reduction in wheat yield (Fang Feng et al., Shandong Agricultural Sciences, 2017, 49(8), 119-123).

[0005] Japanese barnyardgrass (Alopecurus japonicus Steud.) is also a grass weed of the genus Alopecurus. Its plant height is usually higher than that of barnyardgrass. It is a highly harmful weed before or after winter. Its survival competition ability is much stronger than that of barnyardgrass and its damage is more severe. It is also a common malignant grass weed in wheat fields in various parts of China. It is difficult to control and has a great impact on the high and stable yield of wheat (Chen Juan et al., Barley and Cereal Science, 2019, 36(1), 40-42).

[0006] Barnyard grass (Echinochloa crusgalli (L.) Beauv.) is a monocotyledonous grass belonging to the Poaceae family. Due to its extremely high reproductive capacity, it has long been a noxious field weed worldwide, causing crop yield reductions of up to one-third (Guo L, et al. Nat. Comm. 2017, 8(1), 1031). In China, barnyard grass is also the most widely distributed and most harmful field weed to crops, with a particularly prominent impact on rice paddies, bringing severe consequences to agricultural production.

[0007] Since the introduction of chlorsulfuron in the 1970s, dozens of commercially available sulfonylurea herbicides targeting AHAs have emerged. A significant and undeniable fact is that most sulfonylurea herbicides are effective against broadleaf weeds or are non-selective, lacking selective safety for crops. Selective sulfonylurea herbicides with excellent control over grassy weeds are relatively rare. Many common commercially available sulfonylureas have an ester group at the ortho position of the benzene ring, such as chlorsulfuron, mefensulfuron, bensulfuron-methyl, and monosulfuron-methyl. Commercially available herbicides with an ortho-alkoxy substitution at the benzene ring are less common, with only a few types such as ether-bensulfuron-methyl. The structural formulas of these sulfonylurea herbicides are shown below:

[0008]

[0009] Wang Jianguo et al. recently reported two sulfonylurea herbicidal active compounds, CMO and FMO, characterized by alkoxy substituents on the benzene ring. These compounds exhibit excellent control efficacy against barnyard grass and other gramineous weeds (Patent No. ZL 201910960689.5, Authorization Announcement No. CN 110642791 B). Although CMO and ethersulfuron-methyl have very similar structures, computational chemistry results indicate a significant difference in the distribution of their lowest unoccupied molecular orbitals (LUMO), potentially leading to substantial differences in their control efficacy against gramineous weeds (Wang HL, et al. J. Agric. Food Chem., 2021, 69, 8415-8427). The results show that, under the same test conditions, FMO generally demonstrates superior weed control compared to CMO.

[0010] Summary of the Invention

[0011] The purpose of this invention is to provide a class of phenylcycloalkoxy-substituted compounds and their use in the preparation of selective herbicides, particularly their use in the preparation of herbicides safe for wheat and rice against noxious grass weeds such as barnyardgrass, Japanese barnyardgrass, and sedge.

[0012] One type of phenylcycloalkoxy-substituted sulfonylurea compound of the present invention is

[0013]

[0014] The phenylcycloalkoxy-substituted sulfonylurea compound of the present invention is obtained by the following reaction:

[0015]

[0016] 2-Hydroxybenzenesulfonamide A and iodoalkane B were heated under reflux overnight in DMF solution under potassium carbonate catalysis to give 2-alkoxy-substituted benzenesulfonamide C. 2-Amino-4-methoxy-6-methylpyrimidine D and phenyl chloroformate E were reacted in tetrahydrofuran solution at room temperature under potassium carbonate catalysis to give (4-methoxy-6-methylpyrimidine-2-yl)phenyl carbamate F. Intermediates C and F were reacted in acetonitrile solution at room temperature under DBU catalysis to give the target compound G.

[0017] This invention also provides a herbicide for weed control. At an effective dose of 1 gram per acre, applied as a foliar or soil treatment, this herbicide effectively controls a variety of grass and broadleaf weeds, primarily including barnyard grass, goosegrass, American privet, Japanese American privet, crabgrass, rapeseed, and amaranth. At a dose of 2 grams per acre, the herbicide is safe for rice when applied as a soil treatment, or safe for both rice and wheat when applied as a foliar treatment. This herbicide can be used as a selective herbicide in rice or wheat fields, and also as a herbicide in non-agricultural fields such as forest farms or wastelands. The herbicide may contain the aforementioned sulfonylurea compounds and their salts, and its formulation may be an emulsifiable concentrate, wettable powder, soluble powder, emulsion, microemulsion, aqueous solution, suspension concentrate, microcapsule, or water-dispersible granule. It can be applied as a foliar or soil treatment. Attached Figure Description

[0018] Figure 1 This is the high-resolution mass spectrometry (HRMS) spectrum of compound 2022-LA5. Figure 2 This is the HRMS spectrum of compound 2022-LS5. Figure 3 The images show the effects of 2022-LA5, 2022-LS5, and FMO on the control of Japanese wheatgrass when applied to stems and leaves at a dose of 1 gram per acre. Detailed Implementation

[0019] The essential features of the present invention can be seen from the following embodiments, but these embodiments are only illustrative and not intended to limit the invention.

[0020] Example 1. Preparation of compound 2022-LA5

[0021] 1.73 g of o-hydroxybenzenesulfonamide (10 mmol) was added to 15 mL of dimethylformamide, dissolved, and then 6.9 g of potassium carbonate (50 mmol) was added. The mixture was stirred at room temperature for 30 min, followed by the addition of 1.07 mL of 1,1-difluoro-2-iodoethane (11 mmol). The mixture was heated to 105 °C and stirred under reflux for 12 hours. The mixture was then cooled to room temperature, the solid was filtered off, and the filtrate was extracted with water and ethyl acetate. The organic phase was separated, dried, and the solvent was removed under reduced pressure. The mixture was then separated by column chromatography with petroleum ether / ethyl acetate (5:1) to give 1.37 g of a white powdery solid, 2-(2,2-difluoroethoxy)benzenesulfonamide, in 63% yield. This intermediate... 1 The 1H NMR data are as follows: (400 MHz, Acetone-d6), δ 7.86 (dd, J = 7.8, 1.8 Hz, 1H, ArH), 7.62 (ddd, J = 8.1, 7.4, 1.8 Hz, 1H, ArH), 7.34 (dd, J = 8.4, 1.0 Hz, 1H, ArH), 7.17 (td, J = 7.6, 1.0 Hz, 1H, ArH), 6.46 (tt, J = 54.9, 3.8 Hz, 1H, OCH2CHF2), 6.23 (s, 2H, SO2NH2), 4.56 (td, J = 13.8, 3.8 Hz, 2H, OCH2CHF2).

[0022] 7.0 g (50 mmol) of 2-amino-4-methoxy-6-methylpyrimidine was dissolved in 80 mL of tetrahydrofuran, followed by the addition of 11.7 g of potassium carbonate. Then, 9.4 mL (50 mmol) of phenyl chloroformate was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. After the reaction was complete, the filtrate was filtered, the tetrahydrofuran was removed by rotary evaporation, ethyl acetate was added, and the product was separated by column chromatography to give 2.39 g of a white solid (4-methoxy-6-methylpyrimidine-2-yl)carbamate, with a yield of 19%. This intermediate... 1 H NMR data are as follows: 400 MHz, CDCl3) δ 7.98 (s, 1H, NH), 7.39 (t, J = 7.2 Hz, 2H, ArH), 7.24 (s, 1H, ArH), 7.21 (d, J = 7.8 Hz, 2H, ArH), 6.31 (s, 1H, Het-H), 3.97 (d, J = 1.5 Hz, 3H, OCH3), 2.41 (s, 3H, CH3).

[0023] 105 mg (0.44 mmol) of 2-(2,2-difluoroethoxy)benzenesulfonamide was dissolved in 5 mL of acetonitrile. 103 mg (0.4 mmol) of (4-methoxy-6-methylpyrimidin-2-yl)carbamate and 65 μL (0.44 mmol) of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) were added, and the mixture was stirred overnight at room temperature. Then, 10 mL of water was added to the reaction solution, and the pH was adjusted to 2 with 5% hydrochloric acid. A white solid precipitated, which was filtered and dried to give 96.5 mg of product 2022-LA5, with a yield of 46%.

[0024] Similarly, compound 2022-LS5 can be prepared. The reference drug FMO is prepared according to the method disclosed in Chinese Invention Patent CN 110642791 B.

[0025] The physicochemical characterization data of 2022-LA5 and 2022-LS5 are shown in Table 1.

[0026] Table 1. Melting point, properties, and characteristics of the target compound 1 H NMR, 13 C NMR and HRMS data

[0027]

[0028]

[0029] Example 2: Testing the inhibitory activity of the compound on Arabidopsis thaliana acetolactate synthase AHAS.

[0030] The constructed Arabidopsis AHAS catalytic subunit plasmid was transformed into Escherichia coli BL21, and its expression was induced by IPTG. The protein was then purified by immobilized metal affinity chromatography (IMAC). The purified protein was stored at -80°C to maintain its enzyme activity (Hill, CME et al. Biochem. J. 1997, 327, 891-898).

[0031] Preparation of buffer solutions for the system: All cofactors and substrates were prepared as stock solutions and stored at -20℃. FAD was prepared as a 100 μM stock solution, ThDP as 10 mM, MgCl2 as 100 mM, and sodium pyruvate as 500 mM. A 500 mM phosphate buffer solution (pH = 7.0) was prepared. For the inhibition activity assay, 25 μL of each solution was placed in a 1.5 mL centrifuge tube, and 90 μL of Milli-Q purified water, along with 25 μL of solutions of compounds 2022-LA5, 2022-LS5, and FMO at different concentrations, were added.

[0032] AHAS activity assay: 10 μL of Arabidopsis thaliana AHAS enzyme solution was added to the reaction system, initiating the enzyme-catalyzed reaction. The reaction was carried out at 37 °C for 30 min, then terminated by adding 25 μL of 10% H₂SO₄. Heating at 60 °C for 15 min decarboxylated the generated acetolactate, converting it entirely to 3-hydroxy-2-butanone. Then, 250 μL of 5% α-naphthol (dissolved in 4M NaOH solution) and 250 μL of 0.5% creatine solution were added, and the reaction was continued at 60 °C for another 15 min before reading the OD. 525 .

[0033] Suppression constant K i During the assay, for each compound, multiple concentrations must be measured simultaneously within a large and a small time interval to calculate the apparent inhibition constant. Specifically, the concentration of compounds (1-5) in the actual reaction system is first set at 1 × 10⁻⁶. -4 M, 3×10 -5 M, 1×10 -5 M......1×10 -8 M, 3×10 -9 M, 1×10 - 9 M, find the range where the inhibition zone may occur, and then within a small concentration range (e.g., 0, 1×10⁻⁶). -7 M, 1.5 × 10 - 7 M, 2×10 -7 M, 3×10 -7 M, 5×10 -7 M, 7×10 -7 M, 1×10 -6 M, 1.5 × 10 -6 M, 2×10 -6 M, 3×10 -6 M, 5×10 -6 M. (Each measurement was performed in triplicate) to determine the inhibition constant K. i .

[0034] Suppression constant K i Calculated by the following formula

[0035]

[0036] Among them, V max [I] represents the maximum catalytic reaction rate when the AHAS enzyme is not inhibited, [I] represents the concentration of the compound, and V represents the reaction rate.

[0037] The inhibition constants of 2022-LA5, 2022-LS5 and FMO on Arabidopsis thaliana acetolactate synthase AHAS are shown in Table 2.

[0038] Table 2. Inhibition constants of target compound and control drug against Arabidopsis AHAS

[0039] Compound numbering <![CDATA[K of Arabidopsis AHAS i (nM)]]> 2022-LA5 18.04±1.10 2022-LS5 12.24±0.30 FMO 36.00±6.4

[0040] As can be seen from Table 2, the target compounds 2022-LA5 and 2022-LS5 of the present invention have smaller inhibition constants for plant-derived acetolactate synthase (AHAS) compared with the control agent FMO, indicating that they are superior to FMO in inhibiting in vitro AHAS enzymes.

[0041] Example 3. Herbicidal effect of the compound on seven weeds in a pot test model.

[0042] Preparation of medicine solution

[0043] Preparation of emulsified water: First, prepare an emulsion with a concentration of 1‰. Weigh 1g of emulsifier in a beaker, add a small amount of distilled water to dissolve it completely, and then pour it into a 1000mL volumetric flask. Rinse the beaker several times with distilled water, pour the whole solution into the volumetric flask, and finally add distilled water to the mark. Shake well before use.

[0044] Preparation of stock solution: Weigh 30 mg of the test sample and dissolve it completely in 1 mL of DMSO to prepare a 30 mg / mL stock solution. Calculate the dosage according to the spray area, transfer the required volume to a 10 mL beaker, and add the corresponding volume of emulsified water to prepare an aqueous emulsion for spraying. If necessary, dilute stepwise to obtain the required aqueous emulsion for later use.

[0045] Spraying equipment: 3WPSH-500E bioassay spray tower (Nanjing Agricultural Mechanization Research Institute, Ministry of Agriculture and Rural Affairs).

[0046] Potting method: Place a certain amount of soil and water in a 7.0cm diameter paper cup, sow the seeds, cover with a certain thickness of soil, and cultivate in a greenhouse. Cover the seedlings with plastic before they emerge. Water a fixed amount of water daily to maintain normal growth. Test materials: barnyard grass, goosegrass, crabgrass, American privet, Japanese American privet, rapeseed, and amaranth. Treatment time: soil treatment (post-sowing, pre-emergence) and foliar treatment (one leaf and one bud). Results were investigated 21 days after treatment, and the fresh weight of the aboveground parts was measured. The efficacy was expressed as the percentage of fresh weight inhibition. The monocotyledonous weeds used were barnyard grass, goosegrass, American privet, Japanese American privet, and crabgrass; the dicotyledonous weeds were rapeseed and amaranth.

[0047] Table 3 shows the herbicidal effects of the compounds under the test conditions.

[0048] Table 3. Herbicidal effect of the compound at a dose of 1 g / acre in pots (percentage inhibition rate)

[0049]

[0050] As shown in Table 3, at a dosage of 1 g / acre, 2022-LS5 showed better control efficacy against goosegrass than FMO in soil treatment; and at the foliar treatment, 2022-LA5 and 2022-LS5 showed better control efficacy against barnyard grass, Japanese barnyard grass, and barnyard grass than FMO.

[0051] Example 4: Experimental results on the safety of the compound to crops

[0052] The specific experimental details of the soil treatment and foliar treatment methods are the same as in Example 3. The compounds tested were 2022-LA5, 2022-LS5, and FMO. The tested subjects were rice (code name 57#-9) and wheat (code name Xinnong 529).

[0053] Table 4 presents the crop safety results of the tested compounds for wheat and rice.

[0054] Table 4. Crop safety data (percentage inhibition rate) of the tested compounds at a dose of 2 g / acre.

[0055]

[0056] Generally, herbicides with a inhibition rate of less than 5% on crops at a specific dosage are considered safe for crops. Table 4 shows that at a dosage of 2 g / acre, 2022-LA5 is safe for wheat when applied as a foliar herbicide and can be used as a foliar herbicide in wheat fields; 2022-LS5 is safe for wheat when applied as a foliar herbicide and for rice when applied as a soil or foliar herbicide, making it suitable as a soil or foliar herbicide for rice fields and a foliar herbicide for wheat fields; the control herbicide FMO showed extremely high inhibition rates in both rice and wheat under all experimental conditions, but lacked safety and cannot be used for selective weed control in wheat or rice fields under the experimental conditions, whether for soil or foliar application. In comparison, compounds 2022-LA5 and 2022-LS5 of the present invention have better safety for major food crops such as rice and wheat, and can be used as selective herbicides under specific conditions to control common noxious grass weeds in farmland such as barnyard grass, Japanese barnyard grass and barnyard grass.

Claims

1. A phenylcycloalkoxy-substituted sulfonylurea compound, characterized in that... This phenylcycloalkoxy-substituted sulfonyl urea compound is 、 And salts of the above compounds.

2. The use of the phenylcycloalkoxy-substituted sulfonylurea compound of claim 1 and its salt in the preparation of Arabidopsis thaliana acetolactate synthase AHAS inhibitors.

3. Use of the phenylcycloalkoxy-substituted sulfonylurea compound of claim 1 and its salt in the preparation of herbicides.

4. The use according to any one of claims 2-3, characterized in that... The aforementioned Arabidopsis thaliana acetolactate synthase (AHAS) inhibitor or herbicide is effective against barnyard grass, goosegrass, wild oats, and Japanese wild oats.

5. The use according to any one of claims 2-3, characterized in that... The Arabidopsis thaliana acetolactate synthase AHAS inhibitor or herbicide is safe for wheat and rice when applied as a foliar or soil treatment.

6. A herbicide, characterized in that... It contains the phenylcycloalkoxy-substituted sulfonylurea compound of claim 1 and one or more agriculturally acceptable carriers.

7. The herbicide according to claim 6, characterized in that... Its dosage forms include emulsifiable concentrates, wettable powders, soluble powders, water emulsions, microemulsions, aqueous solutions, suspensions, microcapsules, or water-dispersible granules.

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