Oxazoline derivative, preparation method and application thereof

Abstract

The present invention relates to the field of agricultural protection technology, and in particular to an oxazoline derivative, its preparation method, and application. The oxazoline derivative provided by the present invention has n methylene groups inserted between the para position of the 4-benzene ring and the chlorine atom, significantly improving the stability of the oxazoline derivative. The oxazoline derivative provided by the present invention also has excellent mite removal effects, with high activity against mite eggs and nymphs.

Description

Technical Field

[0001] The present invention relates to the technical field of agricultural protection, and in particular to an oxazoline derivative, a preparation method and an application thereof. Background Art

[0002] Phytophagous mites are very harmful to important economic crops such as wheat, corn, soybeans, cotton, fruits, vegetables and flowers. They feed on the leaves, stems and flowers of plants, causing them to wither and yellow, resulting in crop yield reduction and death. Patent CN2019109032142 discloses an oxazoline derivative The high activity against both mite eggs and larvae is primarily due to the significant influence of the para-substituent on the 4-position phenyl ring of the oxazoline on the mite-killing effect. In particular, the insertion of a methylene group between the phenyl ring and the heteroatom significantly alters the activity. This shift in heteroatom position presumably alters the molecular flexibility, thereby altering the binding site and binding capacity with the biological target, ultimately affecting its biological activity. To further enhance the activity of oxazoline derivatives, attempts were made to insert substituents of varying chain lengths between the phenyl ring and the heteroatom, but these substitutions presented different challenges.

[0003] Patent CN 2019109032142: Synthetic intermediate with a methylene group inserted between a benzene ring and a chlorine atom When 4-chloromethylstyrene was reacted with 2,6-difluorobenzonitrile and bromosuccinimide in concentrated sulfuric acid, the yield was optimized to 84%, and the subsequent preparation of the oxazoline intermediate Poor stability. When reacting with RH under alkaline conditions, dehydrochlorination and aromatization of the oxazoline ring to the oxazole ring will occur as a side reaction (Org.Process Res.Dev.2020,24(2),216-227), thus affecting the expected oxazoline derivatives. yield and purity.

[0004] The intermediate prepared by using the patent CN 2019109032142 with only one methylene inserted between the benzene ring and the chlorine atom The analogues with long alkyl chains inserted between the benzene ring and the chlorine atom were prepared by the method of The product cannot be obtained in high yield, and new reaction conditions need to be explored. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems existing in the related art. To this end, the present invention provides an oxazoline derivative comprising One of the following;

[0006] Wherein, n is 2, 3 or 4;

[0007] X is selected from one of S and NH;

[0008] R 4 One selected from methyl, ethyl, n-propyl, phenyl, 2-methoxycarbonylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-methylenedioxyphenyl, 2-naphthyl, 8-quinolyl, 2-methyl-3-furyl, 2-pyridyl or 3-fluoro-2-pyridyl.

[0009] According to the oxazoline derivatives provided by the present invention, X also includes NR 5 ;

[0010] Among them, NR 5 R 4 It is one of N-methylaniline, pyrimidone, benzothiazole, indole, 7-formyl indole, 5-methoxy-7-ethoxycarbonyl indole or 5-chloro-7-ethoxycarbonyl indole.

[0011] The present invention also provides an acaricide comprising the above-mentioned oxazoline derivative.

[0012] The present invention also provides a method for preparing oxazoline derivatives. The preparation method comprises the following steps:

[0013] S21: Pd(PPh3)4 and K2CO3 are placed in a mixed solution of dioxane and water, and heated under reflux and stirring under an inert gas atmosphere to obtain a first mixed solution. The first mixed solution is extracted, dried and concentrated to obtain

[0014] S22: The mixture was placed in dichloromethane and stirred to obtain a second mixed solution. Pyridine was added to the second mixed solution and stirred under an inert gas atmosphere to obtain a third mixed solution. Dichlorothionyl was added to the third mixed solution and heated under reflux to obtain a fourth mixed solution. The fourth mixed solution was quenched, extracted, dried and concentrated to obtain

[0015] S23: The mixture was placed in a mixed solution of acetone and water and stirred to obtain a fifth mixed solution. Bromosuccinimide was added to the fifth mixed solution and stirred to obtain a sixth mixed solution. NH4OAc was added dropwise to the sixth mixed solution and stirred. After concentrating under reduced pressure, the mixture was obtained.

[0016] S24: Place in 2,6-difluorobenzonitrile, stir at 40 ° C to obtain a seventh mixed solution, under an inert gas atmosphere, add concentrated sulfuric acid dropwise to the seventh mixed solution, stir to obtain an eighth mixed solution, quench the eighth mixed solution, extract, dry and concentrate to obtain

[0017] S25: Place in acetonitrile and stir to obtain a ninth mixed solution, add NaOH to the ninth mixed solution, heat and reflux to react, obtain a tenth mixed solution, extract the tenth mixed solution, dry and concentrate to obtain an oxazoline derivative

[0018] S26: Place in acetonitrile and dissolve to obtain the eleventh mixed solution, and R 4 XH, K2CO3 and KI are added to the eleventh mixed solution, and heated under an inert gas atmosphere for reflux reaction to obtain a twelfth mixed solution. The twelfth mixed solution is extracted, dried and concentrated to obtain an oxazoline derivative.

[0019] S27: R 4 OH, K2CO3 and KI are added to the eleventh mixed solution, and heated under reflux reaction in an inert gas atmosphere to obtain a thirteenth mixed solution. The thirteenth mixed solution is extracted, dried and concentrated to obtain an oxazoline derivative.

[0020] According to the preparation method of oxazoline derivatives provided by the present invention, The preparation method further comprises the steps of:

[0021] S31: placing ethyl chlorooxalate in anhydrous dichloromethane and stirring to obtain a fourteenth mixed solution, adding anhydrous aluminum chloride to the fourteenth mixed solution at 0°C and stirring to obtain a fifteenth mixed solution, The dichloromethane solution was added dropwise to the fifteenth mixed solution and stirred to obtain a sixteenth mixed solution. The sixteenth mixed solution was quenched, extracted, dried, and concentrated to obtain

[0022] S32: and hydroxylamine hydrochloride were placed in anhydrous ethanol, stirred and refluxed to obtain a seventeenth mixed solution, the seventeenth mixed solution was extracted, dried and concentrated to obtain

[0023] S33: Place in anhydrous tetrahydrofuran solution and stir to obtain an eighteenth mixed solution. At 0°C, sodium borohydride is added to the eighteenth mixed solution and stirred to obtain a nineteenth mixed solution. The tetrahydrofuran solution of iodine is added dropwise to the nineteenth mixed solution, quenched and refluxed, extracted, dried and concentrated to obtain

[0024] S34: Triethylamine was placed in anhydrous tetrahydrofuran and stirred to obtain a mixed solution. At 0°C, Add the 20th mixed solution and stir to obtain a 21st mixed solution, extract the 21st mixed solution, dry and concentrate to obtain

[0025] S35: and thionyl chloride were placed in dichloromethane, stirred to obtain a twenty-second mixed solution, extracted, dried and concentrated to obtain

[0026] S36: and sodium hydroxide in acetonitrile, stirred to obtain a twenty-third mixed solution, the twenty-third mixed solution was extracted, dried and concentrated to obtain

[0027] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects:

[0028] 1. The present invention provides a method for preparing an oxazoline derivative, wherein The 4-chloroalkylstyrene is first reacted with bromosuccinimide to undergo olefin bromohydroxylation to obtain the intermediate Then react with 2,6-difluorobenzonitrile to obtain the intermediate The two-step yield can reach more than 66%. It has high stability and will not undergo dehydrochlorination when reacting with RH under alkaline conditions, thereby causing the oxazoline ring to aromatize to an oxazole ring.

[0029] 2. The oxazoline derivatives with n of 2 to 4 provided by the present invention have significantly higher mite egg-killing activity than the corresponding oxazoline derivatives with n = 1, have excellent mite removal effects, and have high mite egg and nymph killing activity.

[0030] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0031] To make the purpose, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be described clearly and completely below. Obviously, the embodiments described are part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. The following embodiments are used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0032] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the embodiment of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0033] The present invention provides an oxazoline derivative comprising One of the following;

[0034] Wherein, n is 2, 3 or 4;

[0035] X is selected from one of S and NH;

[0036] R 4 One selected from methyl, ethyl, n-propyl, phenyl, 2-methoxycarbonylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-methylenedioxyphenyl, 2-naphthyl, 8-quinolyl, 2-methyl-3-furyl, 2-pyridyl or 3-fluoro-2-pyridyl.

[0037] The oxazoline derivatives X provided by the present invention also include NR 5 ;

[0038] Among them, NR 5 R 4 It is one of N-methylaniline, pyrimidone, benzothiazole, indole, 7-formyl indole, 5-methoxy-7-ethoxycarbonyl indole or 5-chloro-7-ethoxycarbonyl indole.

[0039] Among them, according to the selection of different substituents, the structural formulas of oxazoline derivatives are shown below and marked as A1-A38, as shown in Table 1:

[0040] Table 1 Structures of oxazoline derivatives

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] As shown in Table 1, A1-A38 were prepared according to the preparation method of oxazoline derivatives provided by the present invention. The corresponding physicochemical data of A1-A38 are shown in Table 2:

[0048] Table 2 Corresponding physical and chemical data of A1-A38

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056] The present invention also provides an acaricide comprising the above-mentioned oxazoline derivative.

[0057] The present invention also provides a method for preparing oxazoline derivatives. The chemical reaction equation is shown below, and this preparation step is named Method 1:

[0058]

[0059] Method 1 The preparation comprises the following steps:

[0060] S21: Pd(PPh3)4 and K2CO3 are placed in a mixed solution of dioxane and water, and heated under reflux and stirring under an inert gas atmosphere to obtain a first mixed solution. The first mixed solution is extracted, dried and concentrated to obtain

[0061] S22: The mixture was placed in dichloromethane and stirred to obtain a second mixed solution. Pyridine was added to the second mixed solution and stirred under an inert gas atmosphere to obtain a third mixed solution. Dichlorothionyl was added to the third mixed solution and heated under reflux to obtain a fourth mixed solution. The fourth mixed solution was quenched, extracted, dried and concentrated to obtain

[0062] S23: The mixture was placed in a mixed solution of acetone and water and stirred to obtain a fifth mixed solution. Bromosuccinimide was added to the fifth mixed solution and stirred to obtain a sixth mixed solution. NH4OAc was added dropwise to the sixth mixed solution and stirred. After concentrating under reduced pressure, the mixture was obtained.

[0063] S24: Place in 2,6-difluorobenzonitrile, stir at 40 ° C to obtain a seventh mixed solution, under an inert gas atmosphere, add concentrated sulfuric acid dropwise to the seventh mixed solution, stir to obtain an eighth mixed solution, quench the eighth mixed solution, extract, dry and concentrate to obtain

[0064] S25: Place in acetonitrile and stir to obtain a ninth mixed solution, add NaOH to the ninth mixed solution, heat and reflux to react, obtain a tenth mixed solution, extract the tenth mixed solution, dry and concentrate to obtain an oxazoline derivative

[0065] S26: Place in acetonitrile and dissolve to obtain the eleventh mixed solution, and R 4 XH, K2CO3 and KI are added to the eleventh mixed solution, and heated under an inert gas atmosphere for reflux reaction to obtain a twelfth mixed solution. The twelfth mixed solution is extracted, dried and concentrated to obtain an oxazoline derivative.

[0066] S27: R 4 OH, K2CO3 and KI are added to the eleventh mixed solution, and heated under reflux reaction in an inert gas atmosphere to obtain a thirteenth mixed solution. The thirteenth mixed solution is extracted, dried and concentrated to obtain an oxazoline derivative.

[0067] Furthermore, The preparation steps are shown in the following examples:

[0068] (1) In a 250 mL round-bottom flask, the starting materials 4-bromophenylethanol (10.05 g, 50 mmol, 1.0 equiv) and vinylboronic acid pinacol ester (9.24 g, 60 mmol, 1.2 equiv) were added, the catalyst Pd(PPh3)4 (2.89 g, 2.5 mmol, 0.05 equiv) and the base K2CO3 (34 g, 250 mmol, 5 equiv) were added, 100 mL of dioxane and 25 mL of water were added as co-solvents, the argon atmosphere was replaced three times, and the mixture was heated under reflux with stirring for 8 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, extracted three times with dichloromethane, and the organic phases were combined and washed once with saturated brine. The palladium catalyst was filtered through diatomaceous earth using an eluent, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Column chromatography was performed using petroleum ether:ethyl acetate = 5:1 as the eluent to obtain 6.42 g of 2-(4-vinylphenyl)ethanol as a colorless oily liquid with a yield of 87%.

[0069] (2) Add the alcohol intermediate 2-(4-vinylphenyl)ethanol (6.42 g, 43.3 mmol, 1.0 equiv) to a 250 mL round-bottom flask, add 100 mL of redistilled dichloromethane to dissolve, add pyridine (4.18 mL, 51.96 mmol, 1.2 equiv), replace the argon atmosphere three times, slowly add dichlorothionyl (3.77 mL, 51.96 mmol, 1.2 equiv) using a syringe while stirring, and heat under reflux for 8 h. After the reaction is completed, water is added to quench the reaction, the liquid is separated, the aqueous phase is extracted three times with dichloromethane, the combined organic phases are washed once with saturated brine, dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. Column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent gives 6.57 g of 1-(2-chloroethyl)-4-vinylbenzene as a colorless oil with a yield of 91%.

[0070] (3) In a 250 mL round-bottom flask, the newly prepared olefin intermediate 1-(2-chloroethyl)-4-vinylbenzene (6.57 g, 39.40 mmol, 1.0 equiv) was added, dissolved in 80 mL of acetone, and 20 mL of water was added as a cosolvent. Bromosuccinimide (NBS, 8.42 g, 47.28 mmol, 1.2 equiv) was added and stirred to disperse. 5 mL of water-dissolved NH4OAc (61 mg, 0.80 mmol, 0.02 equiv) was added dropwise and stirred until the mixture returned to room temperature for 5 h. After the reaction was completed, acetone was removed under reduced pressure, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Column chromatography was performed using petroleum ether: ethyl acetate = 5:1 as the eluent to obtain 8.52 g of 2-bromo-1-(4-(2-chloroethyl)phenyl)ethan-1-ol in a yield of 82% as a white solid with a melting point of 56-58°C.

[0071] (4) The intermediate 2-bromo-1-(4-(2-chloroethyl)phenyl)ethan-1-ol (8.52 g, 32.30 mmol, 1.0 equiv) was added to a 250 mL round-bottom flask, and difluorobenzonitrile was added and heated to about 40°C to dissolve. After the system was completely clear and transparent, it was returned to room temperature, argon was replaced three times, and concentrated sulfuric acid was added dropwise. The mixture was stirred at room temperature for 3 h. After the reaction was completed, a saturated aqueous solution of NaHCO3 was added to quench the reaction. Ethyl acetate was added and extracted three times. The combined organic phases were washed once with saturated brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography using a gradient elution method of petroleum ether:ethyl acetate = 5:1 to 1:1 to obtain 11.19 g of N-(2-bromo-1-(4-(2-chloroethyl)phenyl)ethyl)-2,6-difluoroaniline (yield: 86%). The mixture was a white solid with a melting point of 119-121°C.

[0072] (5) The ring-opening intermediate N-(2-bromo-1-(4-(2-chloroethyl)phenyl)ethyl)-2,6-difluoroaniline (11.19 g, 27.28 mmol, 1.0 equiv) was added to a 250 mL round-bottom flask, dissolved in 80 mL acetonitrile, and then 20 mL NaOH was added. The mixture was heated under reflux until the system gradually became turbid. The reaction was monitored by a plate. The reaction was terminated when most of the raw materials had reacted and by-products appeared. Ethyl acetate was added for extraction three times. The combined organic phases were washed once with saturated brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Column chromatography was performed using petroleum ether:ethyl acetate = 5:1 as the eluent to obtain 7.90 g of 4-(4-(2-chloroethyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole as a light yellow oil with a yield of 90%.

[0073] (6) 4-(4-(2-chloroethyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole (322 mg, 1 mmol, 1.0 equiv) was added to an 8 mL glass bottle, and 3 mL of acetonitrile was added to dissolve it. 2-Hydroxybenzothiazole (181 mg, 1.2 mmol, 1.2 equiv), K2CO3 (166 mg, 1.2 mmol, 1.2 equiv) and KI (199 mg, 1.2 mmol, 1.2 equiv) were added to the bottle, and the mixture was purged with argon and heated under reflux for 8 h. After the reaction was completed, ethyl acetate was added and extracted three times. The combined organic phases were washed once with saturated brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The mixture was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to obtain a yellow oil (3-(4-(2-(2,6-difluorophenyl)-4,5-dihydrooxazol-4-yl)phenethyl)benzo[d]thiazol-2(3H)-one, A8).

[0074] In another embodiment, the preparation method provided in patent CN 2019109032142 is used to synthesize an intermediate in which multiple methylene groups are inserted between the benzene ring and the chlorine atom. When the yield is the highest, it is only 41%.

[0075] The present invention applies to the synthesis New reaction conditions were adopted, and 4-chloroalkylstyrene was first reacted with bromosuccinimide to undergo olefin bromohydroxylation to obtain the intermediate Then react with 2,6-difluorobenzonitrile to obtain the intermediate The two-step yield can reach more than 66%. It has good stability and will not undergo dehydrochlorination when reacting with RH under alkaline conditions, thereby causing the oxazoline ring to aromatize to an oxazole ring.

[0076] According to the preparation method of oxazoline derivatives provided by the present invention, The preparation method also includes the following chemical reaction equation, and its preparation steps are named Method 2:

[0077]

[0078] Method 2 includes the following steps:

[0079] S31: placing ethyl chlorooxalate in anhydrous dichloromethane and stirring to obtain a fourteenth mixed solution, adding anhydrous aluminum chloride to the fourteenth mixed solution at 0°C and stirring to obtain a fifteenth mixed solution, The dichloromethane solution was added dropwise to the fifteenth mixed solution and stirred to obtain a sixteenth mixed solution. The sixteenth mixed solution was quenched, extracted, dried, and concentrated to obtain

[0080] S32: and hydroxylamine hydrochloride were placed in anhydrous ethanol, stirred and refluxed to obtain a seventeenth mixed solution, the seventeenth mixed solution was extracted, dried and concentrated to obtain

[0081] S33: Place in anhydrous tetrahydrofuran solution and stir to obtain an eighteenth mixed solution. At 0°C, sodium borohydride is added to the eighteenth mixed solution and stirred to obtain a nineteenth mixed solution. The tetrahydrofuran solution of iodine is added dropwise to the nineteenth mixed solution, quenched and refluxed, extracted, dried and concentrated to obtain

[0082] S34: Triethylamine was placed in anhydrous tetrahydrofuran and stirred to obtain a mixed solution. At 0°C, Add the 20th mixed solution and stir to obtain a 21st mixed solution, extract the 21st mixed solution, dry and concentrate to obtain

[0083] S35: and thionyl chloride were placed in dichloromethane, stirred to obtain a twenty-second mixed solution, extracted, dried and concentrated to obtain

[0084] S36: and sodium hydroxide in acetonitrile, stirred to obtain a twenty-third mixed solution, the twenty-third mixed solution was extracted, dried and concentrated to obtain

[0085] Furthermore, The preparation steps are shown in the following examples:

[0086] (1) Add ethyl chlorooxalate (3.28 g, 24 mmol) to a 100 mL single-necked bottle and dissolve it in anhydrous dichloromethane (50 mL). Slowly add anhydrous aluminum chloride (5.33 g, 40 mmol) in batches while stirring in an ice bath. Slowly add a dichloromethane solution of 2-ethoxyethylbenzene (2.95 g, 20 mmol) dropwise in an ice bath. Remove the ice bath and stir at room temperature. Monitor the reaction by TLC (PE / EA=4 / 1). The reaction is complete after 5 hours. While stirring, slowly pour the reaction solution into a mixture of 5% dilute hydrochloric acid and ice water to quench the aluminum chloride. Pour the mixture into a separatory funnel for separation, and extract the aqueous phase three times with dichloromethane (20 mL). The organic phases were combined and washed once with water (20 mL) and once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated to obtain 4.13 g of ethyl 2-(4-ethoxyethylphenyl)-2-carbonyl-acetate as a yellow oil with a yield of 84%.

[0087] (2) Add 2-(4-ethoxyethylphenyl)-2-carbonyl-acetic acid ethyl ester (4.00 g, 16 mmol) and hydroxylamine hydrochloride (1.22 g, 17.6 mmol) to a 100 mL single-necked bottle, dissolve in anhydrous ethanol (40 mL), and reflux for 2 h. TLC (PE / EA=4 / 1) monitors the reaction completion. Most of the solvent is removed by vortexing, and water (20 mL) and dichloromethane (20 mL) are added to separate the liquids. The aqueous phase is extracted three times with dichloromethane (20 mL). The combined organic phases are washed once with water (20 mL) and once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated. 2.89 g of 2-(4-ethoxyethylphenyl)-2-hydroxyimino-acetic acid ethyl ester is obtained as a yellow oil by column chromatography with PE / EA=10 / 1, with a yield of 68%.

[0088] (3) Add the above-mentioned 2-(4-ethoxyethylphenyl)-2-hydroxyimino-ethyl acetate (2.12 g, 8 mmol) to a 100 mL single-necked bottle and dissolve it in anhydrous tetrahydrofuran (30 mL). Add sodium borohydride (0.91 g, 24 mmol) under ice bath. Slowly add iodine (3.05 g, 12 mmol) in tetrahydrofuran (10 mL) dropwise under ice bath. After the addition is complete, remove the ice bath and reflux for 8 h. Monitor the reaction by TLC (PE / EA = 1 / 2). The reaction solution was cooled to room temperature, methanol was added dropwise to quench the excess reducing agent, the reaction solution was desolvated, 5% NaOH aqueous solution was added and refluxed for 2 h. After the reaction was completed, water (20 mL) and dichloromethane (20 mL) were added for separation, the aqueous phase was extracted three times with dichloromethane (20 mL), the combined organic phases were washed once with water (20 mL) and once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated to obtain 1.22 g of 2-amino-2-(4-(2-ethoxyethyl)phenyl)ethanol as a yellow oil with a yield of 73%.

[0089] (4) Add the above-mentioned 2-amino-2-(4-(2-ethoxyethyl)phenyl)ethanol (1.22 g, 5.8 mmol) and triethylamine (0.64 g, 6.4 mmol) to a 100 mL single-necked bottle, dissolve in anhydrous tetrahydrofuran (30 mL), add 2,6-difluorobenzoyl chloride (1.12 g, 6.4 mmol) under ice-cooling, react at room temperature for 2 h, and monitor the reaction completion by TLC (PE / EA=3 / 1). Add water (20 mL) and dichloromethane (20 mL) to separate the liquids. The aqueous phase is extracted three times with dichloromethane (20 mL). The combined organic phases are washed once with water (20 mL) and once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated to obtain 1.94 g of N-(1-(4-(2-ethoxyethyl)phenyl)-2-hydroxyethyl)-2,6-difluorobenzamide as a yellow oil with a yield of 96%.

[0090] (5) In a 100 mL single-necked bottle, add the above-mentioned N-(1-(4-(2-ethoxyethyl)phenyl)-2-hydroxyethyl)-2,6-difluorobenzamide (1.50 g, 4.2 mmol) and thionyl chloride (0.60 g, 5 mmol), dissolve in dichloromethane (20 mL), and reflux for 2 h. The reaction is complete after monitoring by TLC (PE / EA=3 / 1). Saturated sodium carbonate solution was added to adjust the pH to 8, water (20 mL) and dichloromethane (20 mL) were added for separation, the aqueous phase was extracted three times with dichloromethane (20 mL), the combined organic phases were washed once with water (20 mL), once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolventized. 1.33 g of N-(2-chloro-1-(4-(2-ethoxyethyl)phenyl)ethyl)-2,6-difluorobenzamide was obtained as a yellow oil with a yield of 86%.

[0091] (6) The above-mentioned N-(2-chloro-1-(4-(2-ethoxyethyl)phenyl)ethyl)-2,6-difluorobenzamide (1.33 g, 3.6 mmol), sodium hydroxide (0.16 g, 4 mmol) and acetonitrile (20 mL) were added to a 100 mL single-necked bottle and dissolved. The mixture was reacted at 50°C for 1 h. The reaction was monitored by TLC (PE / EA=4 / 1). Water (20 mL) and dichloromethane (20 mL) were added for separation. The aqueous phase was extracted three times with dichloromethane (20 mL). The combined organic phases were washed once with water (20 mL) and once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and desolvated. 1.07 g of 2-(2,6-difluorophenyl)-4-(4-(2-ethoxyethyl)phenyl)-4,5-dihydrooxazole (A2) was obtained as a yellow oil by column chromatography with PE / EA=8 / 1. The yield was 90%.

[0092] In one embodiment, the performance of the acaricide provided by the present invention was tested, specifically in the following steps: accurately weighing a sample, adding a small amount of acetone to completely dissolve it, and adding 0.1% Tween-80 water to prepare a stock solution of a certain concentration, which was then diluted with 0.1% Tween-80 water to prepare a series of drug solutions according to the experimental design concentration.

[0093] Mite egg-killing activity was tested using the dipping method on Tetranychus cinnabarinus, reared indoors on bean seedlings. First, potted bean seedlings of uniform size were selected. Appropriate bean leaves were then cut into uniformly sized leaf discs and placed on a Petri dish filled with moisturizing filter paper. Seven female adult mites were placed on each leaf disc to lay eggs. The females were then removed, and the eggs were counted using an electron microscope and numbered for future use. Then, an airbrush was used to evenly spray the eggs, starting with the lowest dose and ending with the highest, according to the experimental design. Three replicates were used for each treatment, with a blank control included. When the blank control eggs were fully hatched, the number of hatched nymphs and unhatched eggs on each leaf disc was counted to calculate the egg hatching inhibition rate.

[0094] Activity against nymphs and larvae: A dip method was used with indoor-reared Tetranychus cinnabarinus mites. Adult mites were inoculated onto newly grown, two-leafed leaves of bean sprouts. The sprouts were cut and placed in a lighted greenhouse at 25°C. Eggs were laid for 24 hours, after which the adult mites were removed and the eggs retained. The eggs were then incubated in the greenhouse for another 5 days until they hatched into larvae. Using tweezers, the entire bean sprout leaf containing larvae was dipped into the prepared test sample for 5-6 seconds. The leaf was removed, the excess liquid shaken off, and placed in a petri dish. The results were analyzed after an additional 4 days of incubation. One plant was dipped in a sample solution containing no test sample and identical additives as a blank control. Each compound was tested in triplicate.

[0095] Etoxazole, ethoxaclonil, NK-12 and FET-II-L were used as positive controls, where NK-12 and FET-II-L are oxazoline derivatives with n=1 provided in patent CN 2019109032142.

[0096] Compounds C1-C4 were used as comparative experiments, and were tested for mite egg and larval mite killing activity against the oxazoline derivatives provided herein. Compounds C1-C4 are oxazoline derivatives containing a methylene group (n=1) and having the same heteroatom substituents as compounds A21, A15, A19, A35, or A29 in this patent, as shown in Table 3.

[0097] Table 3 Comparison of the structures of oxazoline derivatives

[0098]

[0099]

[0100] Furthermore, the comparison of the activity against mite eggs and the hatching inhibition rate is shown in Table 4, and the comparison of the activity against mite larvae and nymphs and the hatching inhibition rate is shown in Table 5.

[0101] Table 4 Comparison of mite egg killing activity

[0102]

[0103]

[0104] Among them, “-” means not tested.

[0105] Table 5 Comparative table of activity against nymphal mites

[0106]

[0107]

[0108] Among them, “-” means not tested.

[0109] As shown in Table 4, at a concentration of 0.1 mg / L, A3-A7, A15, A16, A18, A19, A21-A25, A28, A35, A37, and A38 inhibited the hatching of Tetranychus cinnabarinus eggs by 100%, which was higher than the control, etoxazole, which had a mortality rate of 78.6% at a concentration of 1 mg / L. The test data also showed that compounds with chlorine (A37 and A38), alkoxy (A3-A7), substituted phenoxy or aryloxy (A21-A25), or substituted phenylthio (A15, A16, and A35) at the ethyl, propyl, or butyl position on the 4-position of the phenyl ring of the oxazoline exhibited greater activity than compounds with nitrogen at this position.

[0110] As shown in Table 4, at the concentration of 0.01 mg / L, the mite egg hatching inhibition rates of the highly active compounds FET-II-L and NK-12 were 53.5% and 43.0%, respectively, while the mite egg hatching inhibition rates of A4 (41.7%), A6 (66.2%), A7 (70.2%), A15 (51.5%), A21 (70.6%), A22 (65.6%), A23 (70.8%), A24 (67.1%), A28 (43.0%), and A38 (49.5%) were higher than or equivalent to those of FET-II-L and NK-12.

[0111] As shown in Table 4, at a concentration of 0.025 mg / L, the mite egg hatching inhibition rate of A15 was 100%, which was significantly higher than that of the corresponding control compound C2, whose mite egg hatching inhibition rate at a concentration of 0.025 mg / L was 43.2%.

[0112] As shown in Table 4, at a concentration of 0.1 mg / L, the mite egg hatching inhibition rates of A19 and A35 were 100%, which were significantly higher than those of the corresponding control compound C3, whose mite egg hatching inhibition rate at a concentration of 0.1 mg / L was 61.4%.

[0113] As shown in Table 4, at a concentration of 0.01 mg / L, the mite egg hatching inhibition rate of A21 was 70.8%, slightly higher than that of the corresponding control compound C1, whose mite egg hatching inhibition rate at a concentration of 0.01 mg / L was 68.6%.

[0114] As shown in Table 5, most compounds exhibited 100% mortality against larvae and nymphs at a concentration of 100 mg / L. With decreasing concentrations, the mortality rate decreased rapidly, and overall activity was inferior to that against mite eggs. Compounds A12, A15, A18, A19, A26, A27, and A37 exhibited mortality rates of 46-52% against larvae and nymphs at a concentration of 1.25 mg / L, comparable to the 48.5% mortality rate of FET-II-L at 1.25 mg / L. Compounds A7 (64.5%), A38 (67.4%), A8 (78.0%), A21 (57.5%), A22 (66.7%), A23 (57.6%), and A33 (58.8%) exhibited mortality rates against larvae and nymphs at a concentration of 1.25 mg / L, exceeding that of FET-II-L at the same high concentration.

[0115] As shown in Table 5, the mortality rate of A15 against nymphal mites at a concentration of 1.25 mg / L was 49.0%, which was lower than that of the comparative compound C2 (85.9%) containing one methylene group. This indicates that when the substituent is p-chlorophenylthio, the increase of the methylene group is detrimental to the nymphicidal activity.

[0116] As shown in Table 5, the activity of A19 (45.0%) was comparable to that of the control compound C3 (44.6% mortality at a concentration of 1.25 mg / L), while A35 (15.0%) showed significantly lower activity than C3, indicating that when the substituent is pyridylthio, the increase in the number of methylene groups is detrimental to the larvicidal activity.

[0117] As can be seen from Table 5, compared with the control compound C1 (39.1% mortality of nymphs at a concentration of 1.25 mg / L), the activity of A21 (57.5%) was significantly higher than that of C1, indicating that when the substituent is p-chlorophenyl, the increase of methylene groups is beneficial to the nymphicidal activity.

[0118] As can be seen from Table 5, the activity of A29 (29.6%) was significantly reduced compared to the control compound C4 (42.6% mortality of larvae and nymphs at a concentration of 1.25 mg / L), indicating that when the substituent is indole, the increase of methylene groups is not conducive to the larvicidal activity, which is consistent with the mite egg-killing effect.

[0119] In another embodiment, the insecticidal activity was determined using the following procedure:

[0120] Accurately weigh 20 mg of the compound into a 50 mL beaker, add 200 μL of DMF (analytical grade) to dissolve it, and then add 10 mL of water to prepare a 2000 μg / mL solution. Use tweezers to pick up a cabbage leaf and immerse it for 2-3 seconds, then shake off the excess droplets. Do this one leaf at a time, and prepare 3 cabbage leaves for each sample. Place the samples on absorbent paper in the order marked. After the solution has dried naturally, place it in a marked 10 cm long straight tube, inoculate 2nd instar diamondback moth larvae, seal the tube with gauze, and place it in a standard treatment room. Check the results after 4 days. Repeat 3 times for each compound. The control sample is distilled water with Tween-20 emulsifier and DMF added.

[0121] The results of the test were shown in Table 6 using etoxazole as a control.

[0122] Table 6 Insecticidal activity of compounds

[0123]

[0124]

[0125] As can be seen from Table 6, seven compounds had a mortality rate greater than 80% against Plutella xylostella at a concentration of 200 μg / mL, among which compounds A7 and A34 had a mortality rate of 100% against Plutella xylostella. When the concentration was further reduced to 100 μg / mL, the mortality rate of compound A34 against Plutella xylostella was still 60%, which was comparable to that of etoxazole.

[0126] In summary, since the change in the number of methylene groups between the benzene ring and the heteroatom will cause the change in the flexibility of the molecule, thus changing the binding site and binding ability with the biological target, and ultimately affecting its biological activity, therefore, for X (or O) and R 4 Oxazoline derivatives that are identical but differ only in the number of methylene groups n The mite egg-killing activity of the oxazoline derivatives with n being 2 to 4 provided by the present invention is significantly higher than that of the corresponding oxazoline derivatives with n being 1.

[0127] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. An oxazoline derivative, characterized in that: include 、 or One of the following; Wherein, n is 2, 3 or 4; X is selected from one of S and NH; R 4 One selected from methyl, ethyl, n-propyl, phenyl, 2-methoxycarbonylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-methylenedioxyphenyl, 2-naphthyl, 8-quinolyl, 2-methyl-3-furyl, 2-pyridyl or 3-fluoro-2-pyridyl.

2. The oxazoline derivative according to claim 1, wherein X also includes NR 5 ; Among them, NR 5 R 4 It is one of N-methylaniline, pyrimidone, benzothiazolone, indole, 7-formyl indole, 5-methoxy-7-ethoxycarbonyl indole or 5-chloro-7-ethoxycarbonyl indole.

3. A miticide, characterized in that: The invention comprises an oxazoline derivative as described in any one of claims 1 to 2.

4. A method for preparing an oxazoline derivative according to any one of claims 1 to 2, characterized in that: 、 or The preparation method comprises the following steps: S21: 、 , Pd(PPh3)4 and K2CO3 are placed in a mixed solution of dioxane and water, heated under reflux and stirred in an inert gas atmosphere to obtain a first mixed solution, the first mixed solution is extracted, dried and concentrated to obtain ; S22: The mixture was placed in dichloromethane and stirred to obtain a second mixed solution. Pyridine was added to the second mixed solution and stirred under an inert gas atmosphere to obtain a third mixed solution. Dichlorothionyl was added to the third mixed solution and heated under reflux to obtain a fourth mixed solution. The fourth mixed solution was quenched, extracted, dried and concentrated to obtain ; S23: The mixture was placed in a mixed solution of acetone and water and stirred to obtain a fifth mixed solution. Bromosuccinimide was added to the fifth mixed solution and stirred to obtain a sixth mixed solution. NH4OAc was added dropwise to the sixth mixed solution and stirred. After concentrating under reduced pressure, the mixture was obtained. ; S24: Place in 2,6-difluorobenzonitrile, stir at 40 ° C to obtain a seventh mixed solution, under an inert gas atmosphere, add concentrated sulfuric acid dropwise to the seventh mixed solution, stir to obtain an eighth mixed solution, quench the eighth mixed solution, extract, dry and concentrate to obtain ; S25: Place in acetonitrile and stir to obtain a ninth mixed solution, add NaOH to the ninth mixed solution, heat and reflux to react, obtain a tenth mixed solution, extract the tenth mixed solution, dry and concentrate to obtain an oxazoline derivative ; S26: Place in acetonitrile and dissolve to obtain the eleventh mixed solution, and R 4 XH, K2CO3 and KI are added to the eleventh mixed solution, and heated under an inert gas atmosphere for reflux reaction to obtain a twelfth mixed solution. The twelfth mixed solution is extracted, dried and concentrated to obtain an oxazoline derivative. ; S27: R 4 OH, K2CO3 and KI are added to the eleventh mixed solution, and heated under reflux reaction in an inert gas atmosphere to obtain a thirteenth mixed solution. The thirteenth mixed solution is extracted, dried and concentrated to obtain an oxazoline derivative. .

5. The method for preparing the oxazoline derivatives according to claim 4, wherein The preparation method further comprises the steps of: S31: placing ethyl chlorooxalate in anhydrous dichloromethane and stirring to obtain a fourteenth mixed solution, adding anhydrous aluminum chloride to the fourteenth mixed solution at 0°C and stirring to obtain a fifteenth mixed solution, The dichloromethane solution was added dropwise to the fifteenth mixed solution and stirred to obtain a sixteenth mixed solution. The sixteenth mixed solution was quenched, extracted, dried, and concentrated to obtain ; S32: and hydroxylamine hydrochloride are placed in anhydrous ethanol, stirred and refluxed to obtain a seventeenth mixed solution, the seventeenth mixed solution is extracted, dried and concentrated to obtain ; S33: Place in anhydrous tetrahydrofuran solution and stir to obtain an eighteenth mixed solution. At 0°C, sodium borohydride is added to the eighteenth mixed solution and stirred to obtain a nineteenth mixed solution. The tetrahydrofuran solution of iodine is added dropwise to the nineteenth mixed solution, quenched and refluxed, extracted, dried and concentrated to obtain ; S34: , triethylamine were placed in anhydrous tetrahydrofuran and stirred to obtain a twentieth mixed solution, and at 0 ° C, Add the 20th mixed solution and stir to obtain a 21st mixed solution, extract the 21st mixed solution, dry and concentrate to obtain ; S35: and thionyl chloride were placed in dichloromethane, stirred to obtain a twenty-second mixed solution, extracted, dried and concentrated to obtain ; S36: and sodium hydroxide in acetonitrile, stirred to obtain a twenty-third mixed solution, the twenty-third mixed solution was extracted, dried and concentrated to obtain .

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