CN114853748A - Trifluoromethyl-containing isoxazoline derivative, and preparation method and application thereof - Google Patents

Abstract

The invention relates to a trifluoromethane-containing isoxazoline derivative, a preparation method and application thereof, belonging to the technical field of pesticide chemistry. The chemical structural formula of the trifluoromethane-containing isoxazoline derivative is shown as a general formula I:

wherein R is ^1a 、R ^1b And R ^1c Independently represent any one of hydrogen atom and halogen atom, and the halogen atom represents any one of chlorine atom and fluorine atomSeed; a represents any one of pyrrolyl and B, and B represents any one of phenyl, pyridyl and thiazolyl; r ² Represented by any one of a hydrogen atom and a methyl group; r ³ Is represented by-CH ₂ C(O)NHCH ₂ CF ₃ 、‑OCH ₃ 、‑CH ₂ COOCH ₃ And 6-chloropyrimidinyl. The invention also relates to a preparation method of the trifluoromethane-containing isoxazoline derivative. The invention also applies the trifluoromethane isoxazoline derivative to the preparation of pesticides.

Description

A kind of isoxazoline derivative containing trifluoromethane, its preparation method and application

technical field

The invention relates to the technical field of pesticide chemistry, in particular to a trifluoromethane-containing isoxazoline derivative, a preparation method and application thereof.

Background technique

In the agricultural production process, the use of pesticides is an essential link. For decades, pesticides have played an indelible role in the crafting of human food and in the safety and health of human beings. Pesticide is an indispensable means of production to ensure stable agricultural production and increase income, and it is also a very important strategic material.

Insecticide refers to an agent that kills pests such as beetles, flies, grubs, nose bugs, springtails and nearly ten thousand other pests.

The use of pesticides has gone through several stages: the earliest discovered are natural pesticides and inorganic compounds, but they have a single effect, a large amount, and a short duration of effect; organic synthesis of organic chlorine, organic phosphorus and carbamate Insecticides, which are characterized by high efficiency with high residues or low residues, but many of them have high acute toxicity to mammals.

New insecticides, when first used, tend to have good insecticidal effects, but as the dosage continues to increase and the scope of use continues to expand, cases of rising drug resistance continue to emerge. Existing pesticides, such as permethrin, cypermethrin, beta-cypermethrin, cis-cypermethrin, cyfluthrin, fenvalerate, cis-fenvalerate and fenvalerate, etc., are all neurotoxin insecticides It is also a medium-toxic insecticide, that is, it enters the body of the pest by eating and destroys the nerve conduction function, or after contacting the body of the pest, it causes the pest to be extremely excited, convulsed, paralyzed, and eventually died. However, there are individuals with different degrees of sensitivity to pesticides in natural pest populations. In the process of pesticide use, pesticides are essentially used to select pest populations. The insecticides kill relatively sensitive individuals, resulting in prolonged use or increased dosage of insecticides, resulting in a more or less increase in the resistance level of the pest population.

In the prior art, some isoxazoline derivatives with insecticidal properties are disclosed in EP1,731,512, and Chinese patent CN200880103027.6 discloses isoxazoline compositions and their use as antiparasitic drugs, however , the above-mentioned isoxazoline derivatives of pesticides, pests have developed resistance to them.

In view of this, it is necessary to provide a new insecticide.

SUMMARY OF THE INVENTION

In order to solve the above technical problems, the present invention provides a trifluoromethane-containing isoxazoline derivative, a preparation method and an application. The trifluoromethane-containing isoxazoline derivatives have better insecticidal activity against harmful insects, especially against fruit flies and corn borers, and can be used as insecticides and compositions thereof.

The technical scheme that the present invention solves the above-mentioned technical problems is as follows:

A kind of isoxazoline derivatives containing trifluoromethane, its chemical structure is shown in general formula I:

Wherein, R ^1a , R ^1b and R ^1c are independently represented by any one of a hydrogen atom and a halogen atom, and the halogen atom is represented by any one of a chlorine atom and a fluorine atom;

A represents any one of pyrrolyl and B, and said B represents any one of phenyl, pyridyl and thiazolyl;

R ² represents any one of a hydrogen atom and a methyl group;

R ³ represents any one of -CH ₂ C(O)NHCH ₂ CF ₃ , -OCH ₃ , -CH ₂ COOCH ₃ and 6-chloropyrimidinyl.

The beneficial effects of the trifluoromethane-containing isoxazoline derivatives of the present invention are:

Isoxazoline derivatives containing trifluoromethane have good insecticidal activity against harmful insects, especially for corn borers and fruit flies, can be effectively produced, and can be used as insecticides for harmful insects use.

On the basis of the above technical solutions, the present invention can also be improved as follows.

Further, the chemical structural formulas of the trifluoromethane-containing isoxazoline derivatives are shown in general formula I-1 and general formula I-2:

Wherein, R ^1a , R ^1b and R ^1c are independently represented by any one of a hydrogen atom and a halogen atom, and the halogen atom is represented by any one of a chlorine atom and a fluorine atom;

B represents any one of phenyl, pyridyl and thiazolyl;

R ² represents any one of a hydrogen atom and a methyl group;

R ³ represents any one of -CH ₂ C(O)NHCH ₂ CF ₃ , -OCH ₃ , -CH ₂ COOCH ₃ and 6-chloropyrimidinyl.

The beneficial effect of adopting the above-mentioned further scheme is that the use of chlorine atom and fluorine atom as the halogen atom can further enhance the insecticidal activity of the compound.

Further, the trifluoromethane-containing isoxazoline derivatives include the following specific structural formula:

The beneficial effect of adopting the above-mentioned further scheme is that the compound of the above-mentioned structural formula has better insecticidal activity against corn borer or fruit fly.

The present invention also provides the preparation method of the above-mentioned trifluoromethane-containing isoxazoline derivatives, and the reaction formula is as follows:

Reaction one

Reaction two

Reaction three

Reaction four

Wherein, R ^1a , R ^1b and R ^1c independently represent any one of hydrogen atom and halogen atom; B represents any one of phenyl, pyridyl and thiazolyl;

R ² represents any one of a hydrogen atom and a methyl group;

R ³ represents any one of -CH ₂ C(O)NHCH ₂ CF ₃ , -OCH ₃ , -CH ₂ COOCH ₃ and 6-chloropyrimidinyl;

R ⁴ and R ⁵ are independently represented by any one of methyl and ethyl;

Preparation includes the following steps:

Step A: As shown in reaction formula 1, compound a, halogenated-trifluoro-alkene, catalyst and base are reacted in a solvent to obtain intermediate a;

Step B: as shown in reaction formula 2, react compound b with cuprous cyanide in DMF to obtain intermediate b1; react intermediate b1, hydroxylamine hydrochloride and sodium acetate in ethanol to obtain intermediate c; Body c, sodium nitrite and hydrochloric acid with a mass concentration of 11.5% are reacted to obtain intermediate d1;

Or react compound c, N,N-dimethylformamide and phosphorus oxychloride in dichloromethane to obtain intermediate b2; react intermediate b2 with hydroxylamine hydrochloride and sodium acetate in ethanol to obtain intermediate d2 ;

Step C: As shown in reaction formula 3, the intermediate a of step A, the intermediate d1 of step B and TEA are reacted in DMF to obtain intermediate e1;

Or react the intermediate a of step A, the intermediate d2 of step B, potassium chloride and potassium persulfate in methanol to obtain intermediate e2;

Step D: as shown in reaction formula 4, the intermediate e1 and sodium hydroxide are reacted in ethanol to obtain the intermediate f1; the intermediate f1, DPPA, TEA and R ³ -NH ₂ are reacted in DMF to obtain the general formula The compound shown in I-1;

Or react intermediate e2 and sodium hydroxide in ethanol to obtain intermediate f2; react intermediate f2, DPPA, TEA and R ³ -NH ₂ in DMF to obtain a compound represented by general formula I-2, which is generally The compound represented by the formula I-1 and the compound represented by the general formula I-2 are both trifluoromethane-containing isoxazoline derivatives.

The beneficial effects of adopting the above preparation method are: by adopting the above preparation method, the trifluoromethane-containing isoxazoline derivatives as shown in general formula I can be synthesized, the process route is simple, and the product processing cost is low.

Further, in step A, the molar ratio of the compound a, the halogenated-trifluoro-olefin, the catalyst and the base in the reaction is 1:(1.2-2.0):(0.015-0.03):(1.1 ~1.5), the temperature of the reaction is 80 ~ 90 ℃, and the reaction time is 3 ~ 5h;

The halogenated-trifluoro-alkene is 2-bromo-3,3,3-trifluoro-1-propene;

The solvent is any one or more of tetrahydrofuran, 1,4-dioxane, N,N dimethylformamide, tetrahydrofuran and water;

Described catalyst is any one in tetrakis (triphenylphosphine) palladium and bis (triphenylphosphine) palladium dichloride;

The alkali is any one of sodium carbonate, potassium carbonate and cesium carbonate.

The beneficial effect of adopting the above-mentioned further scheme is: the Suzuki coupling reaction of the raw materials in the above-mentioned proportions can obtain the intermediate a with a higher yield.

Further, in step B, the molar ratio of the compound b to the cuprous cyanide is 1:(1.5-3.0), the reaction temperature is 140-170°C, and the reaction time is 2-8h;

The molar ratio of the intermediate b1, the hydroxylamine hydrochloride and the sodium acetate is 1:(1.1-1.5):(1.1-1.5), the reaction temperature is 70-90°C, and the reaction time is 1-4.5 h;

The molar ratio of the intermediate b2, the hydroxylamine hydrochloride and the sodium acetate is 1:(1.1-1.5):(1.1-1.5), the reaction temperature is 70-90°C, and the reaction time is 1-4.5 h.

The beneficial effect of adopting the above-mentioned further scheme is that: the raw materials in the above proportions are reacted, and the intermediate d1 and the intermediate d2 can be respectively obtained by the reaction, and the reaction efficiency is high.

Further, in step C, the molar ratio of the intermediate a to the intermediate d1 is 1:(1.1-1.8), the reaction temperature is 50-70° C., and the reaction time is 6-12 h.

The beneficial effect of adopting the above-mentioned further scheme is that: the efficiency of the reaction of the raw materials in the above-mentioned proportions to generate the intermediate e1 is high.

Further, in step D, the molar ratio of the intermediate f1, the DPPA, the TEA and the R ³ -NH ₂ is 1:(1.0-1.8):(0.2-0.5):(1.0-1.8 ), the temperature of the reaction is 0°C or 25-35°C, and the reaction time is 10-20h;

The molar ratio of the intermediate f2, the DPPA, the TEA and the R ³ -NH ₂ is 1:(1.0-1.8):(0.2-0.5):(1.0-1.8), and the reaction temperature It is 0℃ or 25～35℃, and the reaction time is 10～20h.

The beneficial effect of adopting the above-mentioned further scheme is: adopting the ratio of the above-mentioned raw materials, the intermediate e1 and the intermediate e2 can be respectively reacted to generate the corresponding compounds of the general formula I-1 and the general formula I-2, and the general formula I-1 and the general formula The compound corresponding to the formula I-2 is the structure corresponding to the general formula I.

The present invention provides the application of a trifluoromethane-containing isoxazoline derivative or a pesticide acceptable salt thereof in the preparation of pesticides.

The beneficial effects are as follows: the trifluoromethane-containing isoxazoline derivatives of the present invention have better insecticidal activity and can effectively kill harmful insects such as corn borers and fruit flies.

Above-mentioned application, described insecticide comprises above-mentioned trifluoromethane isoxazoline derivatives, or its pesticide acceptable salt, and at least one pesticide acceptable excipient; excipient preferably word Any one or more of DMSO, sucrose solution, water and artificial feed, for example, when the corn borer needs to be killed, the artificial feed is used as the excipient of the pesticide of the present invention, and then the corn borer is killed.

Detailed ways

The principles and features of the present invention are described below, and the examples are only used to explain the present invention, but not to limit the scope of the present invention.

Example 1

Compound 1:

The preparation route of compound 1 is as follows:

The preparation of compound 1, specifically:

1. In a 100mL double-necked round bottom flask, add 1.0mol of 3,5-dichlorophenylboronic acid, 1.0mol of 2-bromo-3,3,3-trifluoro-1-propene, 2.0mol of potassium carbonate, 0.015 mmol tetrakis (triphenylphosphine) palladium, 40 mL of tetrahydrofuran, 20 mL of distilled water, under argon protection, heated to reflux at 80 ° C for about 8 h, after monitoring the completion of the reaction by TLC, the reaction solution was cooled to room temperature, 20 mL of distilled water was added, and ethyl acetate was extracted three times , 30 mL each time, the organic phase was dried with anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow liquid, which was separated and purified by silica gel column chromatography to obtain Intermediate 1a;

2. In a 250mL double-necked round-bottomed flask, add 1.0mol of 5-bromopyridine-2-boronic acid, 25mL of N,N-dimethylformamide, and 2.0mol of cuprous cyanide in turn, and stir; the temperature is raised to 170°C After the reaction was completed for 2.5 h, TLC monitoring was completed, the reaction solution was cooled to room temperature, 50 mL of distilled water and 100 mL of ethyl acetate were added and stirred for 1 h; the reaction solution was suction filtered, the filtrate was separated, and the organic phase was retained; the aqueous phase was extracted three times with ethyl acetate , 35 mL each time, the organic phase was washed twice with saturated brine, 20 mL each time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a brown liquid. The crude product was separated and purified by silica gel column chromatography to obtain an intermediate body 1b;

3. In a 100mL single-necked round-bottomed flask, add 1.0mol of intermediate 1d, 25mL of methanol, 1.1mol of hydroxylamine hydrochloride and 1.1mol of sodium acetate in sequence, and heat up to 80°C for reflux reaction for 3h. After monitoring the completion of the reaction by TLC, cool the reaction solution to At room temperature, the methanol was concentrated under reduced pressure to obtain a pale yellow solid. The crude product was separated and purified by silica gel column chromatography to obtain Intermediate 1c;

4. In a 100mL single-neck round-bottom flask, add 1.0mol of intermediate 1c, 30mL of 11.5% dilute hydrochloric acid, take 1.2mol of sodium nitrite, dissolve in distilled water, and slowly add it dropwise to the above reaction solution under ice bath, and in this The reaction was carried out at the same temperature for 3 h, and the reaction was heated to 35 °C and continued to react for 3 h. After monitoring the completion of the reaction by TLC, it was extracted three times with dichloromethane, each 30 mL, and the organic phases were combined and washed twice with saturated brine, each 20 mL, without Dry over magnesium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a yellow solid. The crude product was separated and purified by silica gel column chromatography to obtain the key intermediate 1d;

5. In a 100 mL round-bottomed flask, add 1.0 mol of intermediate 1a, 1.2 mol of intermediate 1d and 10 mL of N,N-dimethylformamide, and then add 2.0 mol of triethylamine dropwise to the above reaction solution to react The temperature of the liquid was raised to 55 °C and the reaction was stirred for 12 h. After the completion of the reaction was monitored by TLC, 20 mL of distilled water was added to the reaction solution and stirred, extracted with ethyl acetate three times, 25 mL each time, the organic phases were combined, and the saturated brine was washed twice, 20 mL each time. , dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a brown liquid, which was separated and purified by silica gel column chromatography to obtain cyclization intermediate 1e;

6. In a 50mL single-neck round-bottom flask, add 1.0mol of intermediate 1e, 15mL of methanol and 5mL of 4N sodium hydroxide solution, the reaction solution is heated to 60°C and refluxed for 3h, after monitoring the completion of the reaction by TLC, concentrate under reduced pressure to remove the methanol solvent , extracted with ethyl acetate three times, 25 mL each time, the organic phases were combined, washed with saturated brine twice, 20 mL each time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 1f;

7. In a 50mL single-neck round-bottom flask, add 1.0mol of intermediate 1f, 5mL of DMF and 1.0mol of diphenyl nitrophosphate, dropwise add 0.2mol of triethylamine under an ice bath, and react at this temperature for 1h, the The reaction solution was warmed to room temperature, 1.0 mol of the compound CF ₃ CH ₂ NH(O)CCH ₂ -NH ₂ hydrochloride was added, and the reaction was stirred for 12 h. After monitoring the completion of the reaction by TLC, 20 mL of distilled water and 40 mL of ethyl acetate were added and stirred for 30 min. The solution layers were separated, the aqueous phase was extracted three times with 25 mL of ethyl acetate, the organic phases were combined, washed with distilled water twice, with 20 mL each, and washed with saturated brine twice, with 20 mL each, and dried over anhydrous sodium sulfate. Suction filtration, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid, which was separated and purified by silica gel column chromatography to obtain compound 1.

The physical properties and mass spectrometry results of compound 1 are as follows:

5-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(2,2,2-trifluoro Ethylamino)-ethyl]-pyridinecarboxamide, white solid, 85.3% yield;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.05 (t, J=6.1 Hz, 1H), 8.94 (d, J=2.1 Hz, 1H), 8.64 (t, J=6.4 Hz, 1H), 8.31 (d, J=8.2Hz, 1H), 8.12 (d, J=8.2Hz, 1H), 7.80 (s, 1H), 7.62 (s, 2H), 4.51 (d, J=18.4Hz, 1H), 4.38 (d, J=18.5Hz, 1H), 3.98 (d, J=6.0Hz, 2H), 3.90 (tt, J=9.9, 4.8Hz, 2H); ¹³ C NMR (101MHz, DMSO-d ₆ )δ169. 94,163.93,156.33,151.50,147.41,139.01,136.54,135.17,130.78,130.12,126.54,126.46,126.14,123.76,122.51,87.68,87.38,43.00,42.63,29.47；HRMS m/z calcd for C ₂₀ H ₁₄ Cl ₂ F ₆ N ₄ O ₃ [M+H] ⁺ 543.0425, found543.0424.

Example 2

Compound 2:

The preparation process of compound 2 is the same as that of Example 1, and the difference between this example and Example is that CF ₃ CH ₂ NH(O)CCH ₂ -NH ₂ in step 7 is replaced by CH ₃ -O-NH ₂ .

The physical properties and mass spectrometry results of compound 2 are as follows:

5-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-methoxy-picolinamide, white solid , the yield is 90.2%;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.22 (s, 1H), 8.90 (s, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.83(s, 1H), 7.64(s, 2H), 4.52(d, J=18.4Hz, 1H), 4.40(d, J=18.5Hz, 1H), 3.72(s, 3H); ¹³ C _{HRMS m / z} F ₃ N ₃ O ₃ [M+H] ⁺ 434.0286, found 434.0283.

Example 3

Compound 3:

The preparation of compound 3 is the same as that of Example 1. The difference between this example and Example 1 is that: CF ₃ CH ₂ NH(O)CCH ₂ -NH ₂ in step 7 is replaced by CH ₃ NHO(O)CCH ₂ - _NH2 .

The physical properties and mass spectrometry results of compound 3 are as follows:

5-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-pyridineglycine methyl ester, white solid, yield 91.4%;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.24(t, J=6.1Hz, 1H), 8.94(s, 1H), 8.31(d, J=10.4Hz, 1H), 8.12(d, J= 8.2Hz, 1H), 7.80(s, 1H), 7.62(s, 2H), 4.51(d, J=18.4Hz, 1H), 4.39(d, J=18.5Hz, 1H), 4.06(d, J= 6.1Hz, 2H), 3.64(s, 3H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ 170.52, 164.08, 156.33, 151.29, 147.52, 139.02, 136.60, 135.17, 130.12, 126.60, 126.15, 125.63, 1225.63 87.70, 87.40, 52.29, 43.01, 41.51; HRMS m/z calcd for C ₁₉ H ₁₄ Cl ₂ F ₃ N ₃ O ₄ [M+H] ⁺ 476.0392, found 476.0390.

Example 4

Compound 4:

The preparation of compound 4 is the same as that of Example 1. The difference between this example and Example 1 is that the 5-bromopyridine-2-boronic acid in step 2 is replaced with 5-bromo(3-methyl)pyridine-2-boronic acid. .

The physical properties and mass spectrometry results of compound 4 are as follows:

5-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-3-methyl-N-[(2,2 ,2-Trifluoroethylamino)-ethyl]-picolinamide, white solid, yield 86.7%;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.92(t, J=6.0Hz, 1H), 8.78(s, 1H), 8.62(t, J=6.3Hz, 1H), 8.10(s, 1H) , 7.82(s, 1H), 7.63(s, 2H), 4.49(s, 1H), 4.37(s, 1H), 3.98–3.89(m, 4H), 2.61(s, 3H); ¹³ C NMR (101MHz) ,DMSO-d ₆ )δ170.06,165.92,156.21,150.24,144.48,139.04,135.17,134.53,130.11,126.56,126.15,125.53,123.79,87.53,87.23,43.07,42.48; C ₂₁ H ₁₆ Cl ₂ F ₆ N ₄ O ₃ [M+H] ⁺ 557.0582, found 557.0581.

Example 5

Compound 5:

The preparation of compound 5 is the same as that of Example 1. The difference between this example and Example 1 is that the 5-bromopyridine-2-boronic acid in step 2 is replaced with 5-bromo(3-methyl)pyridine-2-boronic acid. ; CF3CH2NH(O)CCH2- _NH2 in step ₇ is CF3CH2NH(O _{) CCH2 - NH2} is _{CH3 -} O _{- NH2} .

The physical properties and mass spectrometry results of compound 5 are as follows:

5-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-methoxy-3-methyl-pyridine Formamide, white solid, 91.2% yield;

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.22 (s, 1H), 8.63 (d, J=2.1 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.50 (d, J=1.9 Hz ,2H),7.43(t,J＝1.9Hz,1H),4.09(d,J＝17.3Hz,1H),3.89(s,3H),3.72(d,J＝17.3Hz,1H),2.75(s , 3H); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ 170.64, 166.15, 156.22, 150.15, 144.59, 139.07, 139.03, 135.17, 134.43, 130.13, 126.15, 125.60, 87.54, 81.2, 4, 1.32. ; HRMS m/z calcd for C ₁₈ H ₁₄ Cl ₂ F ₃ N ₃ O ₃ [M+H] ⁺ 448.0443, found448.0437.

Example 6

Compound 6:

The preparation of compound 6 is the same as that of Example 1. The difference between this example and Example 1 is that the 5-bromopyridine-2-boronic acid in step 2 is replaced by 5-bromo(3-methyl)pyridine-2-boronic acid. ; CF ₃ CH ₂ NH(O)CCH ₂ -NH ₂ in step 7 is CH ₃ NHO(O)CCH ₂ -NH ₂ .

The physical properties and mass spectrometry results of compound 6 are as follows:

5-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-3-methyl-pyridineglycine methyl ester, white solid , the yield is 90.9%;

¹ H NMR (400MHz, DMSO-d ₆ )δ9.08(t,J=6.1Hz,1H),8.76(d,J=2.0Hz,1H),8.08(d,J=2.0Hz,1H),7.81 (t, J＝1.9Hz, 1H), 7.61(d, J＝1.9Hz, 2H), 4.48(d, J＝18.4Hz, 1H), 4.35(d, J＝18.5Hz, 1H), 4.01(d , J=6.1Hz, 2H), 3.64(s, 3H), 2.57(s, 3H); ¹³ C NMR (101MHz, DMSO-d ₆ )δ170.64, 166.14, 156.21, 150.13, 144.58, 139.07, 139.03, 135.17, 134.44,130.12,126.15,125.60,87.54,87.24,52.24,43.07,41.33,19.68; HRMS m/z calcd for C ₂₀ H ₁₆ Cl ₂ F ₃ N ₃ O ₄ [M+H] ⁺ 490.0548, found 490.0551.

Example 7

Compound 7:

The preparation of compound 7 is the same as that of Example 1. The difference between this example and Example 1 is that in step 2, the 5-bromopyridine-2-boronic acid used is replaced with 2-bromothiazole-4-boronic acid.

The physical properties and mass spectrometry results of compound 6 are as follows:

2-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(2,2,2-trifluoro Ethylamino)-ethyl]-thiazole-4-carboxamide, white solid, 93.2% yield;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.66(t, J=6.4Hz, 1H), 8.56(t, J=6.1Hz, 1H), 8.52(s, 1H), 7.81(t, J= 1.9Hz, 1H), 7.66 (d, J=1.8Hz, 2H), 4.43 (d, J=18.5Hz, 1H), 4.31 (d, J=18.5Hz, 1H), 3.97 (d, J=6.2Hz) , 2H), 3.90 (td, J=9.8, 6.3 Hz, 2H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 169.89, 160.52, 155.07, 150.94, 138.40, 135.22, 130.24, 128.14, 126.55, 126.15, 123.78 , 88.19, 87.89, 60.22, 43.51, 42.38, 14.54; HRMS m/z calcd for C ₁₈ H ₁₂ Cl ₂ F ₆ N ₄ O ₃ [M+H] ⁺ 548.9990, found 548.9987.

Example 8

Compound 8:

The preparation route of compound 8 is as follows:

The preparation of compound 8, specifically:

1. In a 100ml single-neck round-bottomed flask, add 1.0mol of N,N-dimethylformamide, dropwise add 1.0mol of phosphorus oxychloride under an ice bath, and react at this temperature for 30min, take 1.0mol of 1H- Methyl pyrrole-2-carboxylate was dissolved in 50 ml of CH ₂ Cl ₂ , and added dropwise to the above reaction solution under ice bath. After the dropwise addition, the temperature was raised to 60°C and refluxed for 2 h. After monitoring the completion of the reaction by TLC, the reaction solution was added Cool to room temperature, take 5.0 mol of sodium acetate, dissolve it in 60 mL of distilled water, pour the reaction solution into a 250 mL beaker, add sodium acetate solution under an ice bath, layer the reaction solution, and extract the aqueous phase with dichloromethane three times, 30 mL each time, The organic phase was washed twice with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a yellow solid, which was separated and purified by silica gel column chromatography to obtain Intermediate 8b;

2. In a 100mL single-neck round-bottom flask, add 1.0mol of intermediate 8b, 2.0mol of hydroxylamine hydrochloride, 2.0mol of sodium acetate and 25mL of methanol, heat up to 80°C for reflux reaction for 2h, cool the reaction solution to room temperature, and concentrate under reduced pressure to remove methanol , a pale yellow solid was obtained, which was separated and purified by silica gel column chromatography to obtain intermediate 8d;

3. In a 100mL single-neck round bottom flask, add 0.02mol potassium chloride and 0.2mol potassium hydrogen persulfate, add 20mL distilled water to dissolve, take 1.0mol intermediate a and 1.1mol intermediate 8d of Example 1, add 40mL methanol to dissolve , dropwise into the above reaction solution, stir the reaction at room temperature for 8 h, after monitoring the completion of the reaction by TLC, concentrate under reduced pressure to remove the methanol solvent, extract the remaining aqueous phase with ethyl acetate three times, each 25 mL, combine the organic phases, and wash twice with saturated brine , 20 mL each time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow liquid, which was separated and purified by silica gel column chromatography to obtain intermediate 8e;

4. In a 50mL single-neck round-bottom flask, add 1.0mol of intermediate 8e, 15mL of methanol and 5mL of 4N sodium hydroxide solution, the reaction solution is heated to 60°C and refluxed for 3h. After monitoring the completion of the reaction by TLC, concentrate under reduced pressure to remove methanol The solvent was extracted three times with 25 mL of ethyl acetate, the organic phases were combined, washed twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain Intermediate 8f;

5. In a 50mL single-neck round-bottom flask, add 1.0mol of intermediate 8f, 5mL of DMF and 1.0mol, dropwise add 0.2mol of triethylamine under an ice bath, and react at this temperature for 1h, and the reaction solution is raised to room temperature, 1.0 mol of compound R ³ -NH ₂ hydrochloride was added, and the reaction was stirred for 12 h. After monitoring the completion of the reaction by TLC, 20 mL of distilled water and 40 mL of ethyl acetate were added and stirred for 30 min. The solution was separated, and the aqueous phase was extracted three times with 25 mL of ethyl acetate , the organic phases were combined, washed with distilled water twice, 20 mL each time, saturated brine twice, 20 mL each time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid, which was subjected to silica gel column chromatography After separation and purification, compound 8 was obtained.

The physical properties and mass spectrometry results of compound 8 are as follows:

5-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(2,2,2-trifluoro Ethylamino)-ethyl]-1H-pyrrole-2-carboxamide, pale yellow solid, yield 87.3%;

¹ H NMR (400MHz, DMSO-d ₆ )δ12.08(s,1H),8.69-8.51(m,2H),7.80(s,1H),7.59(s,2H),6.88(s,1H), 6.63 (s, 1H), 4.34 (d, J=18.2Hz, 1H), 4.23 (d, J=18.2Hz, 1H), 3.92 (dd, J=8.7, 6.1Hz, 4H); ¹³ C NMR (101MHz) ,DMSO-d ₆ )δ170.39,160.44,151.50,139.27,135.12,130.52,130.00,126.55,126.12,125.75,123.77,122.92,122.28,113.39,112.96,86.59,.30; for C ₁₉ H ₁₄ Cl ₂ F ₆ N ₄ O ₃ [M+H] ⁺ 531.0425, found 531.0423.

Example 9

Compound 9:

The preparation of compound 9 is the same as that of Example 1, and the difference between this example and Example 1 is:

3,5-dichlorobenzeneboronic acid in step 1 was replaced with 3,4,5-trifluorobenzeneboronic acid; 5-bromopyridine-2-boronic acid in step 2 was replaced with 2-methyl-5-bromopyridine-2 - Boric acid.

The physical properties and mass spectrometry results of compound 9 are as follows:

3-Methyl-5-[5-trifluoromethyl-5-(3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3-yl]-picolinamide, white solid, yield 89.2%;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.92(t, J=6.0Hz, 1H), 8.75(s, 1H), 8.63(t, J=6.4Hz, 1H), 8.07(s, 1H) ,7.71–7.47(m,2H),4.47(d,J＝18.4Hz,1H),4.32(d,J＝18.4Hz,1H),3.92(dd,J＝15.9,6.2Hz,4H),2.58( s, 3H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 170.05, 165.91, 156.13, 150.26, 144.46, 139.02, 134.53, 125.50, 112.91, 112.69, 43.13, 42.46, 19.79; HRMS m/z Hd for C _{21 15} F ₉ N ₄ O ₃ [M+H] ⁺ 543.1079, found 543.1077.

Example 10

Compound 10:

The preparation of compound 10 is the same as that of Example 1, and the difference between this example and Example 1 is:

5-Bromopyridine-2-boronic acid in step 2 was replaced with 2-methyl-5-bromophenylboronic acid: CF3CH2NH(O) _{CCH2 - NH2} in step ₇ was replaced with 4-amino-6- Pyrimidineamine.

The physical properties and mass spectrometry results of compound 10 are as follows:

N-(6-Chloropyrimidin-4-yl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzamide, pale yellow solid, yield 78.6%;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.76(t, J=1.9Hz, 1H), 7.59(d, J=1.9Hz, 2H), 7.29-7.23(m, 2H), 6.60(d, J=8.3Hz, 1H), 5.51(s, 2H), 4.18(d, J=18.1Hz, 1H), 4.09(d, J=18.1Hz, 1H), 2.04(s, 3H); ¹³ C NMR( 101MHz, DMSO-d ₆ ) _{δ157.80,150.25,139.84,135.01,129.83,129.69,126.64,126.23,125.95,123.13,121.14,114.44,113.84,86.17,85.88,43.93,17 14Cl 3} F ₃ N ₄ O ₂ [M+H] ⁺ 529.0213, found 529.0226.

Insecticidal activity test of the compounds obtained in Example 1-10 against corn borer

The insecticidal activities of 10 compounds against the third instar larvae of the corn borer were determined at the concentration of 100 mg/kg and 300 mg/kg by artificial feed mixing method.

1. Reagents and materials:

①Technical drug: Compounds 1-10

②Solvent: DMSO (analytical grade)

③Biomaterials: corn borer, artificial feed

2. Experimental method:

1) Prepare 100mg/kg toxic feed

Dissolve the original drug of the test compound in DMSO, prepare a mother liquor with a concentration of 10,000 mg/kg, mix the mother liquor and artificial feed at a mass ratio of 1:99, and mix thoroughly to prepare an artificial feed containing 100 mg/kg of the drug to be tested. .

2) Prepare 300mg/kg toxic feed

Dissolve the original drug of the test compound in DMSO, prepare a mother liquor with a concentration of 10000mg/kg, mix the mother liquor and artificial feed in a mass ratio of 3:97, and mix thoroughly to prepare an artificial feed containing 300mg/kg of the drug to be tested. .

3) Screening of test insects

The third instar larvae with consistent growth and healthy growth were selected as the test insects.

4) Mixing and receiving insects

Add about 1.0g mixed-toxic artificial feed to each well of the culture plate, and place 20 insects to be tested; after treatment, transfer the culture plate to (26±1°C), relative humidity of 40-70% and photoperiod L/D= The animals were reared under the conditions of 6h/8h (16h and 8h of light and shading, respectively).

5) Inspection and data processing

After 48h and 72h, the death numbers of corn borer were counted. The experiment was repeated 3 times for each drug to be tested, and the number of deaths was counted, and the death rate and corrected death rate were calculated.

Corrected mortality: P ₁ =(P _t -P ₀ )/(1-P ₀ )*100%

In the formula, P _t represents the mortality rate of the experimental group, P ₀ represents the mortality rate of the control group, and P ₁ represents the corrected mortality rate.

3. Experimental results

The insecticidal activities of compounds 1-10 against corn borer at 100 mg/kg are shown in Table 1; the insecticidal activities of compounds 1-10 against corn borer at 300 mg/kg are shown in Table 2.

Table 1:

Table 2:

4. The test results show that:

1) At the concentration of compound 100mg/kg, compounds 1-10 all have insecticidal activity against corn borer, among which compound 4 has the highest insecticidal activity, and compound 1, compound 8, and compound 9 have insecticidal activities at 72h all greater than 40% ;

2) Under the concentration of compound 300mg/kg, compound 1, compound 4, compound 5, compound 6, compound 7, compound 9 and compound 10 all have good insecticidal activity against corn borer, wherein compound 1, compound 4, compound 9 and compound 10 completely killed the corn borer at 72h.

Insecticidal activity test of the compounds obtained in Examples 1-10 on Drosophila

The insecticidal activity of 10 compounds against Drosophila at a concentration of 100 mg/L was tested by IRAC Sensitivity Test No. 026 method.

1. Reagents and materials:

①Technical drug: Compounds 1-10

②Solvent: DMSO (analytical grade)

③ Biological material: Drosophila adult females

2. Experimental method

1) Prepare 100mg/L dilution of the compound to be tested

Dissolve the original drug of the test compound in 100 μL DMSO, prepare a mother solution, and dilute the mother solution with 20% w/v sucrose solution to 100 mg/L of the test compound dilution, each test compound dilution needs about 5mL, to add A 20% sucrose solution in the same amount of solvent (DMSO) served as a control.

2) Screening of test insects

The selected fruit flies were anesthetized with carbon dioxide to determine their sex, and adult females with consistent growth and healthy growth were selected as test insects. After selecting the flies to be tested, they should no longer be stimulated by the external environment (such as high temperature, humidity or starvation).

3) Mixing and receiving insects

A piece of 2 cm dental core was placed in a 175 mL plastic container, and treated with a 20% concentration of sucrose solution (1.2 mL), which was used as a control group. In another identical container, the dental cores were wetted with 1.2 mL of the test compound-containing sucrose solution as the experimental group. Place 10 female flies of uniform size into each container and cover the container with a foam stopper. After treatment, the plastic container was transferred to (23±2)°C, relative humidity 50% and photoperiod L/D=12h/12h (light and shading were treated for 12h respectively).

4) Inspection and data processing

The number of dead flies was counted after 48 hours. The experiment was repeated three times for each drug to be tested, and the number of dead flies in the experimental group and the control group was counted, and the mortality and corrected mortality were calculated.

Corrected mortality: P ₁ =(P _t -P ₀ )/(1-P ₀ )*100%

In the formula, P _t represents the mortality rate of the experimental group, P ₀ represents the mortality rate of the control group, and P ₁ represents the corrected mortality rate.

3. Experimental results

The insecticidal activities of compounds 1-10 against Drosophila at 100 mg/kg are shown in Table 3.

table 3:

Mortality (48h) (%±SEM) Corrected mortality (48h) (%±SEM) Compound 1 100.00±0.00 100.00±0.00 Compound 2 36.67±12.47 33.70±16.49 Compound 3 10.00±8.16 10.00±8.16 Compound 4 100.00±0.00 100.00±0.00 Compound 5 100.00±0.00 100.00±0.00 Compound 6 93.33±4.71 92.96±5.00 Compound 7 23.33±4.71 20.74±1.05 Compound 8 53.33±12.47 51.11±14.99 Compound 9 100.00±0.00 100.00±0.00 Compound 10 96.67±4.71 96.30±5.24

4. The test results show that: at the concentration of compound 100mg/L, compound 1-10 has good insecticidal activity against Drosophila, among which compound 1, compound 4, compound 5, compound 6, compound 8, compound 9 and compound All 10 had high insecticidal activity, and the 48-hour lethality was greater than 92%, among which the 48-hour lethality of compound 1, compound 4, compound 5 and compound 9 reached 100%.

To sum up, the isoxazoline derivatives containing trifluoromethane corresponding to the general formula I of the present invention have good insecticidal activity against Drosophila and Spodoptera litura, and can be used as insecticides.

The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.

Claims (10)

1. a kind of isoxazoline derivatives containing trifluoromethane is characterized in that, its chemical structural formula is as shown in general formula I:

Wherein, R ^1a , R ^1b and R ^1c are independently represented by any one of a hydrogen atom and a halogen atom, and the halogen atom is represented by any one of a chlorine atom and a fluorine atom; A represents any one of pyrrolyl and B, and said B represents any one of phenyl, pyridyl and thiazolyl; R ² represents any one of a hydrogen atom and a methyl group; R ³ represents any one of -CH ₂ C(O)NHCH ₂ CF ₃ , -OCH ₃ , -CH ₂ COOCH ₃ and 6-chloropyrimidinyl. 2. The trifluoromethane-containing isoxazoline derivative according to claim 1, wherein the trifluoromethane-containing isoxazoline derivative comprises general formula I-1 and general formula I-2 Any of the compounds shown in:

Wherein, R ^1a , R ^1b and R ^1c are independently represented by any one of a hydrogen atom and a halogen atom, and the halogen atom is represented by any one of a chlorine atom and a fluorine atom; B represents any one of phenyl, pyridyl and thiazolyl; R ² represents any one of a hydrogen atom and a methyl group; R ³ represents any one of -CH ₂ C(O)NHCH ₂ CF ₃ , -OCH ₃ , -CH ₂ COOCH ₃ and 6-chloropyrimidinyl. 3. The trifluoromethane-containing isoxazoline derivative according to claim 1 or 2, wherein the trifluoromethane-containing isoxazoline derivative comprises any one of the following specific structural formulas:

4. the preparation method containing trifluoromethane isoxazoline derivatives described in any one of claim 1-3, is characterized in that, reaction formula is as follows:

wherein, R ^1a , R ^1b and R ^1c are independently represented by any one of hydrogen atoms and halogen atoms; B represents any one of phenyl, pyridyl and thiazolyl; R ² represents any one of a hydrogen atom and a methyl group; R ³ represents any one of -CH ₂ C(O)NHCH ₂ CF ₃ , -OCH ₃ , -CH ₂ COOCH ₃ and 6-chloropyrimidinyl; R ⁴ and R ⁵ are independently represented by any one of methyl and ethyl; Preparation includes the following steps: Step A: As shown in reaction formula 1, compound a, halogenated-trifluoro-alkene, catalyst and base are reacted in a solvent to obtain intermediate a; Step B: as shown in reaction formula 2, react compound b with cuprous cyanide in DMF to obtain intermediate b1; react intermediate b1, hydroxylamine hydrochloride and sodium acetate in ethanol to obtain intermediate c; Body c, sodium nitrite and hydrochloric acid with a mass concentration of 11.5% are reacted to obtain intermediate d1; Or react compound c, N,N-dimethylformamide and phosphorus oxychloride in dichloromethane to obtain intermediate b2; react intermediate b2 with hydroxylamine hydrochloride and sodium acetate in ethanol to obtain intermediate d2 ; Step C: As shown in reaction formula 3, the intermediate a of step A, the intermediate d1 of step B and TEA are reacted in DMF to obtain intermediate e1; Or react the intermediate a of step A, the intermediate d2 of step B, potassium chloride and potassium persulfate in methanol to obtain intermediate e2; Step D: as shown in reaction formula 4, the intermediate e1 and sodium hydroxide are reacted in ethanol to obtain the intermediate f1; the intermediate f1, DPPA, TEA and R ³ -NH ₂ are reacted in DMF to obtain the general formula The compound shown in I-1; Or react intermediate e2 and sodium hydroxide in ethanol to obtain intermediate f2; react intermediate f2, DPPA, TEA and R ³ -NH ₂ in DMF to obtain a compound represented by general formula I-2, which is generally The compound represented by the formula I-1 and the compound represented by the general formula I-2 are both trifluoromethane-containing isoxazoline derivatives. 5. preparation method according to claim 4 is characterized in that, in step A, the mol ratio of described compound a, described halogenated-trifluoro-alkene, described catalyst and described alkali reaction is 1: ( 1.2～2.0): (0.015～0.03): (1.1～1.5), the temperature of the reaction is 80～90℃, and the reaction time is 3～5h; The halogenated-trifluoro-alkene is 2-bromo-3,3,3-trifluoro-1-propene; The solvent is any one or more of tetrahydrofuran, 1,4-dioxane, N,N dimethylformamide, tetrahydrofuran and water; Described catalyst is any one in tetrakis (triphenylphosphine) palladium and bis (triphenylphosphine) palladium dichloride; The alkali is any one of sodium carbonate, potassium carbonate and cesium carbonate. The preparation method according to claim 4, characterized in that, in step B, the molar ratio of the compound b to the cuprous cyanide is 1:(1.5～3.0), and the reaction temperature is 140 ～170℃, the reaction time is 2～8h; The molar ratio of the intermediate b1, the hydroxylamine hydrochloride and the sodium acetate is 1:(1.1-1.5):(1.1-1.5), the reaction temperature is 70-90°C, and the reaction time is 1-4.5 h; The molar ratio of the intermediate b2, the hydroxylamine hydrochloride and the sodium acetate is 1:(1.1-1.5):(1.1-1.5), the reaction temperature is 70-90°C, and the reaction time is 1-4.5 h. 7. The preparation method according to claim 4, wherein in step C, the molar ratio of the intermediate a to the intermediate d1 is 1:(1.1-1.8), and the reaction temperature is 50 ℃ ～70℃, the reaction time is 6～12h. The preparation method according to claim 4, wherein in step D, the molar ratio of the intermediate f1, the DPPA, the TEA and the R ³ -NH ₂ is 1:(1.0～ 1.8): (0.2～0.5): (1.0～1.8), the temperature of the reaction is 0°C or 25～35°C, and the reaction time is 10～20h; The molar ratio of the intermediate f2, the DPPA, the TEA and the R ³ -NH ₂ is 1:(1.0-1.8):(0.2-0.5):(1.0-1.8), and the reaction temperature It is 0℃ or 25～35℃, and the reaction time is 10～20h. 9. Use of the trifluoromethane-containing isoxazoline derivative according to any one of claims 1 to 3, or a pesticide acceptable salt thereof, in the preparation of pesticides. 10. The application according to claim 9, wherein the pesticide comprises the trifluoromethane-containing isoxazoline derivative according to any one of claims 1-3, or its pesticide acceptable and at least one pesticidally acceptable excipient.