Whitening herbicide structures containing phenoxy-substituted nicotinic acid fragments, methods of making and use thereof

Abstract

The application discloses a compound containing a phenoxy-substituted nicotinic acid fragment structure, a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The compound containing the phenoxy-substituted nicotinic acid fragment structure is shown in the following general formula (I), wherein the preparation method mainly comprises the following steps: contacting a compound shown in the structure of formula (II) in the presence of an alkaline solvent, R 1 and R 2 are each defined as described in the specification. The compound containing the phenoxy-substituted nicotinic acid fragment structure has high herbicidal activity, and has excellent effects on preventing and treating broadleaf weeds and / or gramineous weeds, and the prevention and treatment effects are even better than those of some commercially available commercial herbicides.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to the structure, preparation method and application of an albino herbicide containing phenoxy-substituted nicotinic acid fragments. Background Technology

[0002] p-Hydroxyphenylpyruvate dioxidase (EC 1.13.11.27, HPPD) is a non-heme oxidase found in almost all aerobic organisms. It catalyzes the conversion of p-hydroxyphenylpyruvate (HPPA), produced during tyrosine metabolism, into hydantoin (HGA). The mechanism of action of HPPD-inhibiting herbicides is to inhibit the conversion of HPPA to hydantoin within plants. In plants, hydantoin is further converted into plastoquinone and tocopherol, both essential for electron transport in photosynthesis. Inhibition of HPPD in plants leads to impaired photosynthesis, resulting in bleaching and death.

[0003] Currently developed HPPD-inhibiting herbicides can be classified into five types: triketones, pyrazoles, isoxazoles, diketone nitrs, and benzophenones. Triketones are a class with high herbicidal activity and a broad spectrum of weed control, and many commercial varieties have been successfully developed, such as sulfadiazine, mesotrione, and bicyclosulfadiazine. Among them, mesotrione has many advantages, including a broad spectrum of weed control, high activity, low dosage, good environmental compatibility, low toxicity to mammals and aquatic organisms, excellent safety for corn, and no phytotoxicity to subsequent crop rotation crops. Therefore, HPPD-inhibiting herbicides are a class of herbicides with great research value and development prospects, and have attracted the research and development investment of many pesticide companies.

[0004] Some triketone compounds have been reported as herbicides, see WO2006066871, CN104557739, WO2015058519, CN201410719597.5. However, these herbicides have low safety for crops. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention provides a whitening herbicide containing phenoxy-substituted nicotinic acid fragments, a preparation method and its application, with the aim of solving some of the problems in the prior art or at least alleviating some of the problems in the prior art.

[0006] The present invention is achieved as follows: the first objective of the present invention is to provide a compound containing a phenoxy-substituted nicotinic acid fragment structure, the general structural formula of which is shown in formula (I) below:

[0007]

[0008] Among them, R 1 At least one group selected from H, C1-C6 alkyl groups, trifluoromethyl groups, and halogen groups; R 2 It is derived from one of H, methyl, dimethyl, or phenyl.

[0009] Furthermore, the halogen refers to any one of fluorine, chlorine, and bromine.

[0010] A second object of the present invention is to provide a method for preparing the phenoxy-substituted nicotinic acid fragment compound as described above, wherein the compound with the structure shown in formula (II) is rearranged in the presence of an alkaline solvent.

[0011]

[0012] Among them, R 1 At least one group selected from H, C1-C6 alkyl groups, trifluoromethyl groups, and halogen groups; R 2 It is derived from one of H, methyl, dimethyl, or phenyl.

[0013] Furthermore, the synthetic route for the compound containing phenoxy-substituted nicotinic acid fragments is as follows:

[0014]

[0015] Compound 3 is the compound shown in formula (II) above.

[0016] Furthermore, the synthetic method for obtaining compound 2 from compound 1 can be as follows: under alkaline conditions, compound 1 is reacted with a nucleophile to obtain compound 2.

[0017] In the above reaction, the nucleophile can be any phenol known in the art. The amount of nucleophile relative to compound 1 is preferably 1-2 equivalents, more preferably 1.05-1.1 equivalents. The solvent used in the reaction is dimethylformamide. The reaction temperature is 100°C-150°C, preferably 130°C-140°C. The reaction time is preferably 5-7 hours, more preferably within 5.5 hours.

[0018] Furthermore, the synthesis method for obtaining compound 3 from compound 2 can be as follows: under alkaline conditions, compound 2 is subjected to an esterification reaction with cyclohexanedione or a cyclohexanedione derivative using a condensing agent and a catalyst to obtain compound 3.

[0019] The base used in the esterification reaction described above can be any acid-binding agent known in the art, such as one or more of sodium hydroxide, potassium carbonate, triethylamine, diethylamine, pyridine, and cesium carbonate, preferably triethylamine. The amount of the acid-binding agent relative to the amount of compound 2 is preferably 1.1-1.5 equivalents, more preferably 1.2-1.4 equivalents. The condensing agent used in the esterification reaction can be one or more of dimethylaminotetrahydropyrazole carboxylate, dicyclohexylcarbodiimide, diimide hydrochloride, and diisopropylcarbodiimide, preferably diimide hydrochloride. The catalyst used in the esterification reaction can be one or more of 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and 4-dimethylaminopyridine, preferably 4-dimethylaminopyridine. The ratio of the condensing agent to the catalyst used in the reaction is preferably 5:1 to 15:1 equivalents, more preferably 10:1 equivalents. The solvent used in the esterification reaction can be dichloromethane, chloroform, N,N-dimethylformamide, or dimethyl sulfoxide, etc. The temperature of the esterification reaction is preferably 20-30°C, more preferably 20-25°C. The time of the esterification reaction is preferably 0.5-2 hours, more preferably within 1 hour.

[0020] Furthermore, the method for synthesizing compound (I) from compound 3 is as follows: under rearrangement reaction conditions, compound 3 is contacted with a rearrangement reagent to obtain compound (I).

[0021] The synthetic method for obtaining compound I from compound 3 can be as follows: under rearrangement reaction conditions, compound 3 is contacted with a rearrangement reagent to obtain compound I. The rearrangement reagent can be any one of potassium cyanide, sodium cyanide, aluminum trichloride, and acetone cyanohydrin, preferably acetone cyanohydrin. The amount of the rearrangement reagent relative to the amount of compound 3 is preferably 0.5-1.5 equivalents, more preferably 0.8-1.2 equivalents. The temperature of the rearrangement reaction is preferably 0℃-40℃, more preferably 20℃-25℃. The time of the rearrangement reaction is preferably 3-12 hours, more preferably within 5-6 hours.

[0022] A third objective of this invention is to provide the use of the above-mentioned phenoxy-substituted nicotinic acid fragment compounds in the control of weeds or in the preparation of herbicides.

[0023] Furthermore, the weeds are at least one of broadleaf weeds and grass weeds.

[0024] A fourth object of the present invention is to provide the use of the phenoxy-substituted nicotinic acid fragment compound as described above as an HPPD-inhibiting herbicide.

[0025] In summary, the advantages and positive effects of this invention are as follows:

[0026] This invention provides a structure of albino herbicide containing phenoxy-substituted nicotinic acid fragments and a method for its preparation. The compound of this invention maintains excellent herbicidal activity while still exhibiting high safety activity against wheat.

[0027] The whitening herbicides containing phenoxy-substituted nicotinic acid fragments provided by this invention exhibit excellent inhibitory activity against p-hydroxyphenylpyruvate dioxygenase. These herbicides also demonstrate particularly superior herbicidal activity against weeds such as barnyard grass, ryegrass, foxtail grass, amaranth, velvetleaf, and lambsquarters. Furthermore, the triketone compounds containing phenoxy-substituted nicotinic acid fragments of this invention exhibit high herbicidal activity, particularly effective against broadleaf weeds and / or grass weeds, with control effects even surpassing some commercially available herbicides. Detailed Implementation

[0028] 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. Unless otherwise specified, the equipment and reagents used in the embodiments and experimental examples are commercially available. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention.

[0029] This invention discloses the structure, preparation method, and application of a whitening herbicide containing phenoxy-substituted nicotinic acid fragments. In the following examples, NMR data were measured using an AVANVE 500MHz NMR spectrometer, and mass spectrometry data were measured using a microOTOF-Q II 10410 mass spectrometer.

[0030] Example 1: Preparation of 3-oxocyclohexyl-1-en-1-yl 6-phenoxynicotinate

[0031] Step A: Preparation of 6-phenoxynicotinic acid

[0032] 30 mmol of 2-chloronicotinic acid, 39.0 mmol of phenol, and 30 mL of dimethylformamide were added to a 150 mL three-necked flask and refluxed at 135 °C for 5.5 hours. After cooling, 100 mL of deionized water was added. The pH was adjusted to 2-4 with 10 wt% dilute hydrochloric acid, dried, and passed through a column with ethyl acetate / petroleum ether as the eluent (1 / 4, v / v) to give a white solid.

[0033] Step B: Preparation of 3-oxocyclohexyl-1-en-1-yl 6-phenoxynicotinic acid ester

[0034] 10.0 mmol of 6-phenoxynicotinic acid and 11.0 mmol of cyclohexanedione were added to a 150 mL three-necked flask, followed by the addition of 30 mL of dichloromethane and stirring. The mixture was heated to 25 °C, and then 1.3 equivalents of triethylamine, 2 equivalents of diimine hydrochloride as condensing agents, and 0.2 equivalents of 4-dimethylaminopyridine as a catalyst were added, and the reaction was continued for 0.5 h. The mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated sodium chloride. After drying, the mixture was passed through a column chromatography system using ethyl acetate / petroleum ether as the eluent (1 / 3, v / v) to give a white solid.

[0035] Example 2 Preparation of 3-oxocyclohexyl-1-en-1-yl 6-(3-chlorophenoxy)nicotinic acid ester

[0036] Step A: Preparation of 6-(3-chlorophenoxy)nicotinic acid

[0037] 30.0 mmol of 2-chloronicotinic acid, 39.0 mmol of 3-chlorophenol, and 30 mL of dimethylformamide were added to a 150 mL three-necked flask and refluxed at 135 °C for 5.5 hours. After cooling, 100 mL of deionized water was added. The pH was adjusted to 2-4 with 10 wt% dilute hydrochloric acid, dried, and purified by column chromatography using ethyl acetate / petroleum ether at a volume ratio of 1 / 4 to give a white solid.

[0038] Step B: Preparation of 3-oxocyclohexyl-1-en-1-yl 6-(3-chlorophenoxy)nicotinic acid ester

[0039] 10.0 mmol of 6-(3-chlorophenoxy)nicotinic acid and 11.0 mmol of cyclohexanedione were added to a 150 mL three-necked flask, followed by the addition of 30 mL of dichloromethane and stirring. The mixture was heated to 25 °C, and then 1.3 equivalents of triethylamine, 2 equivalents of diimine hydrochloride as condensing agents, and 0.2 equivalents of 4-dimethylaminopyridine as a catalyst were added, and the reaction was continued for 0.5 h. The mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated sodium chloride. After drying, the mixture was passed through a column chromatography system using ethyl acetate / petroleum ether as the eluent (1 / 3, v / v) to give a white solid.

[0040] Example 3 Preparation of 3-oxocyclohexyl-1-en-1-yl 6-(3-fluorophenoxy)nicotinic acid ester

[0041] Step A: Preparation of 6-(3-fluorophenoxy)nicotinic acid

[0042] 30.0 mmol of 2-chloronicotinic acid, 39.0 mmol of 3-fluorophenol, and 30 mL of dimethylformamide were added to a 150 mL three-necked flask and refluxed at 135 °C for 5.5 hours. After cooling, 100 mL of deionized water was added. The pH was adjusted to 2-4 with 10 wt% dilute hydrochloric acid, dried, and purified by column chromatography using ethyl acetate / petroleum ether at a volume ratio of 1 / 4 to give a white solid.

[0043] Step B: Preparation of 3-oxocyclohexyl-1-en-1-yl 6-(3-fluorophenoxy)nicotinic acid ester

[0044] 10.0 mmol of 6-(3-fluorophenoxy)nicotinic acid and 11.0 mmol of cyclohexanedione were added to a 150 mL three-necked flask, followed by the addition of 30 mL of dichloromethane and stirring. The mixture was heated to 25 °C, and then 1.3 equivalents of triethylamine, 2 equivalents of diimine hydrochloride as condensing agents, and 0.2 equivalents of 4-dimethylaminopyridine as a catalyst were added, and the reaction was continued for 0.5 h. The mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated sodium chloride. After drying, the mixture was passed through a column chromatography eluent of ethyl acetate / petroleum ether = 1 / 3 (v / v) to give a white solid.

[0045] Example 4 Preparation of 3-oxocyclohexyl-1-en-1-yl 6-(3-(trifluoromethyl)phenoxy)nicotinic acid ester

[0046] Step A: Preparation of 6-(3-(trifluoromethyl)phenoxy)nicotinic acid

[0047] 30.0 mmol of 2-chloronicotinic acid, 39.0 mmol of 3-(trifluoromethyl)phenol, and 30 mL of dimethylformamide were added to a 150 mL three-necked flask and refluxed at 135 °C for 5.5 hours. After cooling, 100 mL of deionized water was added. The pH was adjusted to 2-4 with 10 wt% dilute hydrochloric acid, dried, and purified by column chromatography using ethyl acetate / petroleum ether at a volume ratio of 1 / 4 to give a white solid.

[0048] Step B: Preparation of 3-oxocyclohexyl-1-en-1-yl 6-(3-(trifluoromethyl)phenoxy)nicotinic acid ester

[0049] 10.0 mmol of 6-(3-(trifluoromethyl)phenoxy)nicotinic acid and 11.0 mmol of cyclohexanedione were added to a 150 mL three-necked flask, followed by the addition of 30 mL of dichloromethane and stirring. The mixture was heated to 25 °C, and then 1.3 equivalents of triethylamine, 2 equivalents of diimine hydrochloride as condensing agents, and 0.2 equivalents of 4-dimethylaminopyridine as a catalyst were added, and the reaction was continued for 0.5 h. The mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated sodium chloride. After drying, the mixture was passed through a column chromatography eluent of ethyl acetate / petroleum ether = 1 / 3 (v / v) to give a white solid.

[0050] Example 5 Preparation of 3-oxocyclohexyl-1-en-1-yl 6-(m-tolyloxy)nicotinic acid ester

[0051] Step A: Preparation of 6-(m-Tolyloxy)nicotinic acid

[0052] 30.0 mmol of 2-chloronicotinic acid, 39.0 mmol of m-methylphenol, and 30 mL of dimethylformamide were added to a 150 mL three-necked flask and refluxed at 135 °C for 5.5 hours. After cooling, 100 mL of deionized water was added. The pH was adjusted to 2-4 with 10 wt% dilute hydrochloric acid, dried, and passed through a column with ethyl acetate / petroleum ether as the eluent (1 / 4, v / v) to give a white solid.

[0053] Step B: Preparation of 3-oxocyclohexyl-1-en-1-yl 6-(m-tolyloxy)nicotinic acid ester

[0054] 10.0 mmol of 6-(m-tolyloxy)nicotinic acid and 11.0 mmol of cyclohexanedione were added to a 150 mL three-necked flask, followed by the addition of 30 mL of dichloromethane and stirring. The mixture was heated to 25 °C, and then 1.3 equivalents of triethylamine, 2 equivalents of diimine hydrochloride as condensing agents, and 0.2 equivalents of 4-dimethylaminopyridine as a catalyst were added, and the reaction was continued for 0.5 h. The mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated sodium chloride. After drying, the mixture was passed through a column chromatography system using ethyl acetate / petroleum ether as the eluent (1 / 3, v / v) to give a white solid.

[0055] Example 6 Preparation of 5-methyl-3-oxocyclohex-1-en-1-yl 6-phenoxynicotinic acid ester

[0056] Step A: Preparation of 6-phenoxynicotinic acid

[0057] 30.0 mmol of 2-chloronicotinic acid, 39.0 mmol of phenol, and 30 mL of dimethylformamide were added to a 150 mL three-necked flask and refluxed at 135 °C for 5.5 hours. After cooling, 100 mL of deionized water was added. The pH was adjusted to 2-4 with 10 wt% dilute hydrochloric acid, dried, and purified by column chromatography using ethyl acetate / petroleum ether at a volume ratio of 1 / 4 to give a white solid.

[0058] Step B: Preparation of 5-methyl-3-oxocyclohex-1-en-1-yl-6-phenoxynicotinic acid ester

[0059] 10.0 mmol of 6-phenoxynicotinic acid and 11.0 mmol of 5-methylcyclohexane-1,3-dione were added to a 150 mL three-necked flask, followed by the addition of 30 mL of dichloromethane and stirring. The mixture was heated to 25 °C, and then 1.3 equivalents of triethylamine, 2 equivalents of diimine hydrochloride as condensing agents, and 0.2 equivalents of 4-dimethylaminopyridine as a catalyst were added, and the reaction was continued for 0.5 h. The mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated sodium chloride. After drying, the mixture was passed through a column chromatography system using ethyl acetate / petroleum ether as the eluent (1 / 3, v / v) to give a white solid.

[0060] Example 7 Preparation of 5,5-dimethyl-3-oxocyclohex-1-en-1-yl-6-phenoxynicotinate

[0061] Step A: Preparation of 6-phenoxynicotinic acid

[0062] 30.0 mmol of 2-chloronicotinic acid, 39.0 mmol of phenol, and 30 mL of dimethylformamide were added to a 150 mL three-necked flask and refluxed at 135 °C for 5.5 hours. After cooling, 100 mL of deionized water was added. The pH was adjusted to 2-4 with 10 wt% dilute hydrochloric acid, dried, and purified by column chromatography using ethyl acetate / petroleum ether at a volume ratio of 1 / 4 to give a white solid.

[0063] Step B: Preparation of 5,5-dimethyl-3-oxocyclohex-1-en-1-yl-6-phenoxynicotinate

[0064] 10.0 mmol of 6-phenoxynicotinic acid and 11.0 mmol of 5,5-dimethylcyclohexane-1,3-dione were added to a 150 mL three-necked flask, followed by the addition of 30 mL of dichloromethane and stirring. The mixture was heated to 25 °C, and then 1.3 equivalents of triethylamine, 2 equivalents of diimine hydrochloride as condensing agents, and 0.2 equivalents of 4-dimethylaminopyridine as a catalyst were added, and the reaction was continued for 0.5 h. The mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated sodium chloride. After drying, the mixture was passed through a column chromatography system using ethyl acetate / petroleum ether as the eluent (1 / 3, v / v) to give a white solid.

[0065] Example 8 Preparation of 5-oxo-1,2,5,6-tetrahydro-[1,1'-biphenyl]-3-yl6-phenoxynicotinic acid ester

[0066] Step A: Preparation of 6-phenoxynicotinic acid

[0067] 30.0 mmol of 2-chloronicotinic acid, 39.0 mmol of phenol, and 30 mL of dimethylformamide were added to a 150 mL three-necked flask and refluxed at 135 °C for 5.5 hours. After cooling, 100 mL of deionized water was added. The pH was adjusted to 2-4 with 10 wt% dilute hydrochloric acid, dried, and purified by column chromatography using ethyl acetate / petroleum ether at a volume ratio of 1 / 4 to give a white solid.

[0068] Step B: Preparation of 5-oxo-1,2,5,6-tetrahydro-[1,1'-biphenyl]-3-yl6-phenoxynicotinic acid ester

[0069] 10.0 mmol of 6-phenoxynicotinic acid and 11.0 mmol of 5-phenyl-1,3-cyclohexanedione were added to a 150 mL three-necked flask, followed by the addition of 30 mL of dichloromethane and stirring. The mixture was heated to 25 °C, and then 1.3 equivalents of triethylamine, 2 equivalents of diimine hydrochloride as condensing agents, and 0.2 equivalents of 4-dimethylaminopyridine as a catalyst were added, and the reaction was continued for 0.5 h. The mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated sodium chloride. After drying, the mixture was passed through a column chromatography system using ethyl acetate / petroleum ether as the eluent (1 / 3, v / v) to give a white solid.

[0070] Example 9 Rearrangement Reaction

[0071] 8.0 mmol of 3-oxocyclohexyl-1-en-1-yl 6-phenoxynicotinic acid ester obtained in Example 1 of this invention was placed in a 150 mL three-necked flask, and 13 equivalents of acetonitrile and 1 equivalent of acetone cyanohydrin were added. At 25 °C, 1.2 equivalents of triethylamine, an acid-binding agent, was slowly added dropwise. After reacting for approximately 6 hours, the mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated brine. The solution was dried, eluted with petroleum ether / ethyl acetate = 6 / 1 (volume ratio), to give a white solid. mp 126.6-126.8 °C. 1 H NMR(500MHz,CDCl3)δ(ppm)16.67(s,1H,OH),8.20-8.19(m,1H,Ar-H),7.75-7.73(m,1H,Ar-H),7.39-7.36(m,2H,Ar-H),7.21-7.18(m,1H,Ar-H),7.11 -7.07(m,2H,Ar-H),7.06-7.05(m,1H,Ar-H),2.73-2.70(t,J=11.4Hz,2H,CH2),2.42-2.39(t,J=10.6Hz,2H,CH2),1.99-1.97(m,2H,CH2); HRMS(ES+)C 18 H 15 NO4[M+H] + Calculated value: 310.1080; Measured value: 310.1074. The structural formula is as follows:

[0072]

[0073] Example 10 Rearrangement Reaction

[0074] 8.0 mmol of 3-oxocyclohexyl-1-en-1-yl 6-(3-chlorophenoxy)nicotinic acid ester obtained in Example 2 of this invention was placed in a 150 mL three-necked flask, and 13 equivalents of acetonitrile and 1 equivalent of acetone cyanohydrin were added. At 25 °C, 1.2 equivalents of triethylamine, an acid-binding agent, was slowly added dropwise. After reacting for approximately 6 hours, the mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated brine. The solution was dried, eluted with petroleum ether / ethyl acetate in a 6 / 1 (volume ratio), to give a white solid. mp 116.5-116.9 °C. 1 HNMR(500MHz,CDCl3)δ(ppm)16.90(s,1H,OH),8.38-8.37(m,1H,Ar-H),7.89-7.87(m,1H,Ar-H),7.35-7.34(m,1H,Ar-H),7.22-7.21(m,2H,Ar-H),7. 09-7.07(m,1H,Ar-H),6.93-6.91(m,1H,Ar-H),2.75-2.74(t,J=2.6Hz,2H, CH2),2.51-2.50(t,J=3.1Hz,2H,CH2),2.07-2.04(m,2H,CH2); HRMS(ES+)C 18 H 14 ClNO4[M+H] + Calculated value: 344.0690; Measured value: 344.0683. The structural formula is as follows:

[0075]

[0076] Example 11 Rearrangement Reaction

[0077] 8.0 mmol of 3-oxocyclohexyl-1-en-1-yl 6-(3-fluorophenoxy)nicotinic acid ester obtained in Example 3 of this invention was placed in a 150 mL three-necked flask, and 13 equivalents of acetonitrile and 1 equivalent of acetone cyanohydrin were added. At 25 °C, 1.2 equivalents of triethylamine, an acid-binding agent, was slowly added dropwise. After reacting for approximately 6 hours, the mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated brine. The solution was dried, eluted with petroleum ether / ethyl acetate = 6 / 1 (volume ratio), to give a white solid. mp 98.4-99.1 °C. 1H NMR (500MHz, CDCl3) δ (ppm) 16.90 (s, 1H, OH), 8.36-8.37 (m, 1H, Ar-H), 7.91-7.89 (m, 1H, Ar-H), 7.54-7.45 (m, 3H, Ar-H), 7.37-7.36 (m, 1H, Ar- H),6.96-6.95(m,1H,Ar-H),2.76-2.74(t,J=6.3Hz,2H,CH2),2.51-2.49(t,J=6.6Hz,2H,CH2),2.07-2.04(t,J=11.4Hz,2H,CH2); HRMS(ES+)C 18 H 14 FNO4[M+H] + Calculated value: 328.0986; Measured value: 328.0979. The structural formula is as follows:

[0078]

[0079] Example 12 Rearrangement Reaction

[0080] 8.0 mmol of 3-oxocyclohexyl-1-en-1-yl 6-(3-(trifluoromethyl)phenoxy)nicotinic acid ester obtained in Example 4 of this invention was placed in a 150 mL three-necked flask, and 13 equivalents of acetonitrile and 1 equivalent of acetone cyanohydrin were added. At 25 °C, 1.2 equivalents of triethylamine, an acid-binding agent, were slowly added dropwise. After reacting for approximately 6 hours, the mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated brine. The solution was dried, eluted with petroleum ether / ethyl acetate = 6 / 1 (volume ratio), to give a white solid. mp 102.8-103.2 °C. 1 H NMR (500MHz, CDCl3) δ (ppm) 16.91 (s, 1H, OH), 8.36-8.35 (m, 1H, Ar-H), 8.00-7.98 (m, 1H, Ar-H), 7.52-7.48 (m, 3H, Ar-H), 6.97-6.95 (m, 1H, Ar- H),6.87-6.86(m,1H,Ar-H),2.77-2.74(t,J=6.3Hz,2H,CH2),2.52-2.49(t,J=6.6Hz,2H,CH2),2.09-2.04(d,J=16.4Hz,2H,CH2); HRMS(ES+)C 19 H 14 F3NO4[M+H] + Calculated value: 378.0954; Measured value: 378.0945. The structural formula is as follows:

[0081]

[0082] Example 13 Rearrangement Reaction

[0083] 8.0 mmol of 3-oxocyclohexyl-1-en-1-yl 6-(m-tolyloxy)nicotinic acid ester obtained in Example 5 of this invention was placed in a 150 mL three-necked flask, and 13 equivalents of acetonitrile and 1 equivalent of acetone cyanohydrin were added. At 25 °C, 1.2 equivalents of triethylamine, an acid-binding agent, was slowly added dropwise. After reacting for approximately 6 hours, the mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated brine. The solution was dried, eluted with petroleum ether / ethyl acetate in a 6 / 1 (volume ratio), to give a white solid. The mp value was 95.6-96.1 °C. 1 H NMR(500MHz,CDCl3)δ(ppm)16.82(s,1H,OH),8.49-8.48(m,1H,Ar-H),7.77-7.74(m,1H,Ar-H),7.36-7.34(m,2H,Ar-H),7.22-7.20(m,1H,Ar-H),7.06 -7.05(m,2H,Ar-H),2.96-2.94(d,J=6.6Hz,2H,CH2),2.52-2.51(d,J=2.6Hz,2H,CH2),2.28-2.26(d,J=6.7Hz,2H,CH2),2.17(s,3H,CH3); HRMS(ES+)C 19 H 17 NO4[M+H] + Calculated value: 324.1237; Measured value: 324.1229. The structural formula is as follows:

[0084]

[0085] Example 14 Rearrangement Reaction

[0086] 8.0 mmol of 5-methyl-3-oxocyclohexyl-1-en-1-yl 6-phenoxynicotinic acid ester obtained in Example 6 of this invention was placed in a 150 mL three-necked flask, and 13 equivalents of acetonitrile and 1 equivalent of acetone cyanohydrin were added. At 25 °C, 1.2 equivalents of triethylamine, an acid-binding agent, was slowly added dropwise. After reacting for approximately 6 hours, the mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated brine. The solution was dried, eluted with petroleum ether / ethyl acetate in a 6 / 1 (volume ratio), to give a white solid. The mp values ​​were 117.3-117.6 °C. 1HNMR (500MHz, CDCl3) δ (ppm) 16.90 (s, 1H, OH), 8.38-8.37 (m, 1H, Ar-H), 7.89-7.86 (m, 1H, Ar-H), 7.37-7.34 (m, 2H, Ar-H ),6.98-6.92(m,4H,Ar-H),2.60-2.36(m,4H,2CH2),2.20-2.17(m,1H,CH),1.26-1.24(d,J=7.2Hz,3H,CH3); HRMS(ES+)C 19 H 17 NO4[M+H] + Calculated value: 324.1237; Measured value: 324.1230. The structural formula is as follows:

[0087]

[0088] Example 15 Rearrangement Reaction

[0089] 8.0 mmol of 5,5-dimethyl-3-oxocyclohexyl-1-en-1-yl 6-phenoxynicotinic acid ester obtained in Example 7 of this invention was placed in a 150 mL three-necked flask, and 13 equivalents of acetonitrile and 1 equivalent of acetone cyanohydrin were added. At 25 °C, 1.2 equivalents of triethylamine, an acid-binding agent, was slowly added dropwise. After reacting for approximately 6 hours, the mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated brine. The solution was dried, eluted with petroleum ether / ethyl acetate = 6 / 1 (volume ratio), to give a white solid. mp 109.1-109.6 °C. 1 H NMR (500MHz, CDCl3) δ (ppm) 16.54 (s, 1H, OH), 8.40-8.39 (m, 1H, Ar-H), 8.09-8.07 (m, 1H, Ar-H), 7.43-7.40 (m, 2H Ar-H),7.24-7.22(m,1H,Ar-H),7.16-7.15(m,2H,Ar-H),7.08-7.07(m,1H,Ar-H),2.36-2.32(d,J=16.3Hz,4H,2CH2),1.04(s,6H,2CH3); HRMS(ES+)C 20 H 19 NO4[M+H] + Calculated value: 338.1393; Measured value: 338.1386. The structural formula is as follows:

[0090]

[0091] Example 16 Rearrangement Reaction

[0092] 8.0 mmol of 5-oxo-1,2,5,6-tetrahydro-[1,1'-biphenyl]-3-yl6-phenoxynicotinic acid ester obtained in Example 8 of this invention was placed in a 150 mL three-necked flask, and 13 equivalents of acetonitrile and 1 equivalent of acetone cyanohydrin were added. At 25 °C, 1.2 equivalents of triethylamine, an acid-binding agent, was slowly added dropwise. After reacting for approximately 6 hours, the mixture was washed three times with 10 wt% dilute hydrochloric acid and three times with saturated brine. The solution was dried, eluted with petroleum ether / ethyl acetate = 6 / 1 (volume ratio), to give a white solid. mp 129.8-130.2 °C. 1 H NMR (500MHz, CDCl3) δ (ppm) 17.08 (s, 1H, OH), 8.20-8.18 (m, 1H, Ar-H), 7.56-7.74 (m, 1H, Ar-H), 7.39-7.36 (m, 4H, Ar-H),6.99-6.91(m,7H,Ar-H),2.73-2.70(m,2H,CH2),2.42-2.39(m,1H,CH),1.99-1.97(m,2H,CH2); HRMS(ES+)C 24 H 19 NO4[M+H] + Calculated value: 386.1393; Measured value: 386.1384. The structural formula is as follows:

[0093]

[0094] Following a similar method, a series of compounds were synthesized as shown in the table below, all of which were confirmed by NMR and high-resolution mass spectrometry.

[0095]

[0096] R in the structural formula 1 and R 2 The groups represented are shown in Table 1:

[0097] Table 1: R in the structural formula 1 and R 2 The group represented

[0098]

[0099]

[0100] Note: Yield is the yield after the final purification step.

[0101] Example 17: Inhibitory activity test of whitening herbicides containing phenoxy-substituted nicotinic acid fragments against HPPD.

[0102] This embodiment describes enzyme activity testing according to the methods described in "Ind. Crops Prod. 2019, 137, 566-575 and J. Agric. Food Chem. 2010, 58, 2643-2651". The results showed the inhibitory activity (IC50) of the whitening herbicide containing phenoxy-substituted nicotinic acid fragments of this invention against p-hydroxyphenylpyruvate dioxygenase (Arabidopsis thaliana source, AtHPPD) and the control requirements. 50 The results are shown in Table 2.

[0103] Table 2: Comparison of the inhibitory activities of whitening herbicides containing phenoxy-substituted nicotinic acid fragments and control compounds against AtHPPD.

[0104] Serial Number <![CDATA[IC 50 (μM)]]> Serial Number <![CDATA[IC 50 (μM)]]> Mesotrione 0.278 I-19 7.027 I-1 4.078 I-20 4.729 I-2 6.968 I-21 0.212 I-3 8.292 I-22 2.201 I-4 5.212 I-23 5.254 I-5 5.129 I-24 0.999 I-6 7.727 I-25 0.738 I-7 9.178 I-26 2.963 I-8 5.741 I-27 5.751 I-9 6.858 I-28 1.279 I-10 9.032 I-29 0.188 I-11 10.235 I-30 1.368 I-12 7.128 I-31 3.418 I-13 1.488 I-32 0.754 I-14 4.746 I-33 0.672 I-15 6.761 I-34 2.015 I-16 3.288 I-35 4.988 I-17 3.276 I-36 1.091 I-18 5.986

[0105] The results shown in Table 2 indicate that the above compounds have good inhibitory activity against AtHPPD. I-21, I-25, I-29, I-32, and I-33 exhibit excellent activity, especially I-29, which is far superior to the commercially available control agent mesotrione.

[0106] Example 18 Herbicidal Activity Experiment

[0107] This embodiment is used to illustrate the herbicidal activity inhibition rate (%) of the compound containing phenoxy-substituted nicotinic acid fragment structure described in this invention (dosage is 150 g / ha).

[0108] Initial screening test: The test targets were velvetleaf, amaranth, lambsquarters, barnyard grass, foxtail grass, and ryegrass. A certain amount of soil that had passed through a 2mm sieve was used to evenly sow the selected, plump, peeled weed seeds on the soil, cover them with a layer of soil about 1cm thick, and water them appropriately. The weeds were then grown under room temperature and artificial light conditions. Water was added daily to maintain soil moisture at approximately 80%, the growth temperature was 25-30℃, and the air humidity was above 70%. The weeds were allowed to grow to approximately the 3-leaf stage before use. The prepared test solutions of each compound were evenly sprayed on the leaves at a dosage of 150 g / ha. The weeds were allowed to continue growing under artificial light conditions for 10 days before the results were investigated. The inhibition rate (%) is shown in Table 3.

[0109] Table 3 Comparison of herbicidal activity inhibition rates (%) of compounds containing phenoxy-substituted nicotinic acid fragment structures

[0110]

[0111]

[0112] From the above results, it can be seen that when R 1 When R is an electron-withdrawing group, it is beneficial to improve the inhibitory activity of the compound, and R 1The stronger the electron-withdrawing ability of the compound, the higher its inhibitory activity, and compounds substituted at the middle position are more active than those substituted at the para position. 2 Unsubstituents exhibit better inhibitory activity than substituents.

[0113] The results shown in Table 3 indicate that the above compounds have higher overall activity against velvetleaf, amaranth, barnyard grass, foxtail grass, and ryegrass than the control herbicide mesotrione. In addition, they can also control grassy weeds such as foxtail grass that mesotrione cannot control.

[0114] Example 19 Safety Experiment

[0115] This embodiment illustrates the safety of the whitening herbicide containing phenoxy-substituted nicotinic acid fragments described in this invention. Test crops: cotton, peanut, wheat, rice, and corn.

[0116] Greenhouse small-cup method: Take a certain amount of soil that has passed through a 5mm sieve, soak the selected crop seeds in warm water for 12 hours, and then place them in a 25℃ incubator for 24 hours to germinate. Select 5-8 uniform and well-germinated crop seeds, place them evenly on the soil surface with the hilum facing down, and cover them with about 10g of dry soil. Incubate at 26.5℃, 75% humidity, and 12 hours of light and 12 hours of darkness in a cycle. All treatments were repeated three times. Different concentrations of the newly synthesized compound were sprayed at the 3-4 leaf stage, and the agent was applied as a foliar spray. After application, the plants were placed in a greenhouse for observation. One week later, the chlorophyll content of the crop stems and leaves was measured to determine the crop's safety and activity.

[0117] Table 4 Comparison of the effects of different compounds on chlorophyll content (mg / g) in crop stems and leaves

[0118]

[0119]

[0120] As shown in Table 4, all of the above compounds can be used as herbicides, and compounds 21 and 29 are significantly safer for wheat fields at a dosage of 300 g / ha than the commercially available herbicide mesotrione.

[0121] The data above show that the triketone compounds containing phenoxy-substituted nicotinic acid fragments prepared by this invention have herbicidal effects, especially in controlling broadleaf weeds or grass weeds, and have high crop safety.

[0122] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound containing phenoxy-substituted nicotinic acid fragment structures, characterized in that: The general structural formula of the compound containing phenoxy-substituted nicotinic acid fragment structure is shown in formula (I) below: ； Among them, R 1 At least one group selected from H, C1-C6 alkyl groups, trifluoromethyl groups, and halogen groups; R 2 Derived from one of H, methyl, dimethyl, or phenyl; The halogen refers to any one of fluorine, chlorine, and bromine.

2. The method for preparing the compound containing phenoxy-substituted nicotinic acid fragment structure as shown in general formula (I) according to claim 1, characterized in that: The synthetic route for the compound containing the phenoxy-substituted nicotinic acid fragment structure is as follows: 。 3. The method for preparing the compound containing phenoxy-substituted nicotinic acid fragment structure according to claim 2, characterized in that: The method for synthesizing compound 2 from compound 1 is as follows: under alkaline conditions, compound 1 is reacted with a nucleophile to obtain compound 2.

4. The method for preparing the compound containing phenoxy-substituted nicotinic acid fragment structure according to claim 2, characterized in that: The method for synthesizing compound 3 from compound 2 is as follows: under alkaline conditions, compound 2 is subjected to an esterification reaction with cyclohexanedione or a cyclohexanedione derivative using a condensing agent and a catalyst to obtain compound 3. The condensing agent is one or more of dimethylaminotetrahydropyrazole carboxylate, dicyclohexylcarbodiimide, diimide hydrochloride, and diisopropylcarbodiimide; The catalyst is one or more of 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and 4-dimethylaminopyridine.

5. The method for preparing the compound containing phenoxy-substituted nicotinic acid fragment structure according to claim 2, characterized in that: The synthetic method for obtaining compound (I) from compound 3 is as follows: under rearrangement reaction conditions, compound 3 is contacted with a rearrangement reagent to obtain compound (I). The rearrangement reagent is any one of potassium cyanide, sodium cyanide, aluminum trichloride, and acetone cyanohydrin.

6. The use of the compound containing phenoxy-substituted nicotinic acid fragment structure as described in claim 1 as a 4-HPPD inhibitor.

7. The use of the compound containing phenoxy-substituted nicotinic acid fragment structure as described in claim 1 in the control of weeds or in the preparation of herbicides.

8. The application according to claim 7, characterized in that: The weeds are at least one of broadleaf weeds and grass weeds.

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