Guanidyl-containing 5-chloroindan compound as well as preparation method and application thereof

Abstract

The invention discloses a guanidyl-containing 5-chloroindan compound as well as a preparation method and application thereof. The structural formula of the compound is as shown in formula I in the specification. The invention designs and synthesizes a novel compound containing 5-chloroindan and guanidyl active fragments. An activity determination result shows that the compound has efficient insecticidal activity on insects such as plutella xylostella and the like. The invention has important significance on agricultural pest control, and can provide a new and efficient control means for agricultural production. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of new pesticide creation, and specifically relates to a guanidine-containing 5-chloroindane compound and a preparation method and application thereof. Background Art

[0002] Agriculture is the foundation of human survival and development, and pesticides, as an important part of agricultural production, play a key role in increasing crop yields and ensuring food security. However, traditional pesticide molecules often have many problems, such as environmental pollution, crop resistance, toxicity to non-target organisms, etc. These problems restrict the further application and development of pesticides. Therefore, it is of far-reaching significance to create new pesticides and delay the development of commercial pesticide resistance. Indoxacarb is a highly effective insecticide developed by DuPont in the United States that acts on the sodium ion channel of insects. However, in the process of agricultural pest control, due to the long-term use of indoxacarb, problems such as resistance and environmental pollution have become increasingly prominent. Summary of the invention

[0003] One of the purposes of the present invention is to provide a compound containing 5-chloroindane and a guanidine active fragment and a synthesis method thereof.

[0004] The compound containing 5-chloroindane and guanidino active fragment provided by the present invention has a structural formula as shown in Formula I:

[0005] In formula I, R can be: -C substituted with 0, 1, 2, 3, 4 or 5 groups selected from the following 1-6 Alkyl or C 3-6 Cycloalkyl: halogen, amino, C 1-6 Alkoxy; C 1-6 or aryl or aryl substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of halogen, nitro, amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-4 Halogenated alkyl; wherein the aryl group includes phenyl, naphthyl, furyl; Specifically, R can be one of methyl, ethyl, cyclopropane, methylamino, n-propyl, phenyl, m-fluorophenyl, p-methylphenyl, m-methoxyphenyl, p-bromophenyl, m-trifluoromethylphenyl, p-nitrophenyl, m-chlorophenyl, o-chlorophenyl, naphthyl, methoxyethyl, and 2-furan.

[0006] In some embodiments of the present invention, the compound represented by formula I is selected from any one of the following compounds: .

[0008] The compound represented by the above formula I is prepared by a method comprising the following steps: (1) 5-chloro-1-indanone represented by formula II undergoes a reductive amination reaction with ammonium acetate in the presence of a reducing agent to obtain a compound represented by formula III;

[0009] (2) In the presence of a condensing agent and a catalyst, the compound represented by formula III reacts with Boc-glycine to remove Boc to obtain a compound represented by formula V;

[0010] (3) under alkaline conditions, the isomethylthiourea hemisulfate represented by formula VI reacts with di-tert-butyl dicarbonate represented by formula VII to obtain the mono-Boc-protected isomethylthiourea represented by formula VIII;

[0011] (4) Under alkaline conditions, the mono-Boc-protected isomethylthiourea reacts with the acyl chloride represented by formula IX to obtain the compound represented by formula X;

[0012] In Formula IX and Formula X, R is as defined above; (5) Under alkaline conditions, the compound represented by formula V reacts with the compound represented by formula X to remove Boc to obtain the compound represented by formula I.

[0013] In step (1) of the above method, the reducing agent is sodium cyanoborohydride. The reaction is carried out in an organic solvent, and the organic solvent can specifically be isopropanol. After the reaction is completed, the reaction solution needs to be quenched with sodium hydroxide aqueous solution.

[0014] In step (2), the condensation agent is EDCI or DCC, and the catalyst is DMAP; The reaction is carried out in an organic solvent, and the organic solvent may specifically be dichloromethane.

[0015] In step (3), the reaction is carried out in a solvent, and the solvent used is a mixture of two solvents in a volume ratio of 1:1 to 5:1, and the two solvents are dioxane / water, tetrahydrofuran / water or acetone / water; The alkali used is any one of sodium bicarbonate, sodium carbonate, potassium carbonate or sodium hydroxide.

[0016] In step (4), the reaction temperature is 0°C-25°C, and the reaction is carried out in a solvent, wherein the solvent used is dichloromethane, toluene, DMF or acetone; and the base used can be any one of triethylamine, 4-DMAP and potassium carbonate.

[0017] In step (5), the reaction is carried out in a solvent, the solvent used is DMF, dioxane or tetrahydrofuran, and the reaction temperature is 25°C-70°C.

[0018] The second object of the present invention is to provide the use of the compound represented by the above formula I in preventing and controlling agricultural pests.

[0019] The application is that the compound represented by formula I is suitable for preventing and controlling beet armyworm, diamondback moth, cabbage looper, cutworm, cabbage armyworm, cotton bollworm, tobacco budworm and leaf roller on crops.

[0020] Among them, the crops include cabbage, kale, tomato, pepper, cucumber, apple, pear, peach, apricot, cotton, potato, grape, tea and corn.

[0021] The present invention also provides an insecticide, which contains the compound shown in the above formula I or takes the compound shown in the above formula I as an active ingredient.

[0022] The present invention designs and synthesizes a novel compound containing 5-chloroindane and guanidine active fragments, and the activity test results show that the compound has a highly effective insecticidal activity against insects such as diamondback moth. The present invention has important significance for the prevention and control of agricultural diseases and insect pests, and can provide a new and efficient control method for agricultural production. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the compound prepared in Example 1 of the present invention.

[0024] Figure 2 This is the carbon NMR spectrum of the compound prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0025] The present invention is further described in detail below in conjunction with specific embodiments, and the examples provided are only for illustrating the present invention, rather than for limiting the scope of the present invention. The examples provided below can be used as a guide for further improvements by those of ordinary skill in the art, and do not constitute a limitation of the present invention in any way.

[0026] The experimental methods in the following examples, unless otherwise specified, are all conventional methods, and are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial channels.

[0027] Example 1. Preparation of Compound A4

[0028] Weigh 3 mmol of the compound of formula II and 10 eq of ammonium acetate in a 100 ml round-bottom flask, add 30 ml of isopropanol to the round-bottom flask and stir at room temperature for 1 hour. After stirring for 1 hour, add 3.5 eq of sodium cyanoborohydride to the flask, and heat the mixture to reflux temperature. Reflux and stir for 3 hours. After stopping heating, add sodium hydroxide solution to the solution to quench the reaction, concentrate to remove isopropanol, and then use ethyl acetate to extract the reaction solution, collect the organic phase, dry it over anhydrous sodium sulfate, concentrate the solvent, and pass it through a column. Use petroleum ether / ethyl acetate = 1:1 eluent to collect the yellow oily product III, with a yield of 48%.

[0029] The structural confirmation data are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 7.18 – 7.14 (m,1H), 7.10 (d, J = 6.9 Hz, 2H), 4.23 (t, J = 7.6 Hz, 1H), 2.84 (ddd, J = 15.9, 8.5,3.2 Hz, 1H), 2.70 (dt, J = 16.2, 8.4 Hz, 1H), 2.42 (dtd, J = 12.5, 7.5, 3.2 Hz,1H), 1.62 (tt, J = 12.1, 7.5 Hz, 1H), 1.45 (s, 2H). 13 C NMR (126 MHz, CDCl3) δ 144.97, 144.05, 131.83, 125.63, 123.80,123.46, 55.74, 36.60, 28.93.

[0030] (a) Weigh 1 mmol of the compound of formula III and place it in a 100 ml round-bottom flask. Add dichloromethane and stir to dissolve it. Then add 1.2 eq of the compound of formula IV and 1.5 eq of EDCI. After stirring for a while, add 0.1 eq of DMAP to the solution. After stirring at room temperature for 3 hours, wash with deionized water and saturated brine, collect the organic phase, dry it with anhydrous sodium sulfate, concentrate the solvent, pass it through a column, and use petroleum ether / ethyl acetate = 3:1 as an eluent to collect the white solid product.

[0031] (b) trifluoroacetic acid was added to the collected product, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the trifluoroacetic acid was concentrated, and the remaining trifluoroacetic acid was neutralized with a saturated sodium bicarbonate aqueous solution. The reactant was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was concentrated. The product (compound represented by formula V) was drained, and the yield was 85%.

[0032] The structural confirmation data are as follows: 1 H NMR (500 MHz, DMSO- d 6) δ 8.76 (d, J = 8.0 Hz, 1H),8.10 (s, 2H), 7.34 (d, J = 1.7 Hz, 1H), 7.28 – 7.22 (m, 2H), 5.28 (q, J = 7.8 Hz,1H), 3.63 – 3.55 (m, 2H), 2.95 (ddd, J = 16.2, 8.7, 3.7 Hz, 1H), 2.84 (q, J = 8.1Hz, 1H), 2.46 – 2.41 (m, 1H), 1.83 (dq, J = 12.7, 8.5 Hz, 1H). 13 C NMR (126 MHz, DMSO- d 6) δ 166.30, 146.04, 142.84, 132.72, 126.85,126.06, 125.08, 53.84, 40.69, 33.32, 30.08.

[0033] Dissolve 0.15 mol of isomethylthiourea hemisulfate and 0.15 mol of sodium bicarbonate in 40 ml of solvent (V THF :V H2O =1:1), 0.1 mol of Boc anhydride represented by formula VII was slowly added dropwise under ice-water bath and stirring conditions, the addition was completed in 20 minutes, and the reaction was continued with stirring at room temperature for 1 hour. After the reaction was completed, tetrahydrofuran was concentrated to remove tetrahydrofuran, and the residue was extracted with dichloromethane, the dichloromethane phase was collected, dried over anhydrous sodium sulfate, and the solvent was concentrated. After the solvent was concentrated, it was passed through a column to collect the white solid product VIII, and the yield was 69%.

[0034] The structural confirmation data are as follows: 1 H NMR (500 MHz, Chloroform- d) δ 2.39 (s, 3H), 1.44 (s, 9H). 13 C NMR (126 MHz, Chloroform- d ) δ 171.9, 160.6, 79.1,27.6,12.7.

[0035] 0.1 mol of mono-Boc anhydride protected isomethylthiourea shown in formula VIII and 0.2 mol of triethylamine were dissolved in 40 ml of dichloromethane. Under ice bath stirring condition, 0.2 mol of p-methylbenzoyl chloride-dichloromethane solution was slowly added dropwise into the reaction flask. After the addition was completed, stirring was continued. After the reaction was completed, water was added to extract the reaction solution under spot plate monitoring. The dichloromethane phase was collected, dried over anhydrous sodium sulfate, and the concentrated solvent was passed through a column. The white solid product was collected using an eluent of petroleum ether / ethyl acetate = 100:1. The yield was 80%.

[0036] The structural confirmation data are as follows: 1 HNMR (500 MHz, Chloroform- d ) δ 12.47 (s, 1H), 8.08 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 2.46 (s, 3H), 2.33 (s, 3H), 1.44(s, 9H). 13 C NMR (126 MHz, Chloroform- d ) δ 175.03, 170.51, 150.07, 142.54,133.02, 129.22, 128.00, 82.32, 26.98, 20.67, 13.87.

[0037] (a) 1.5 mmol of the compound represented by formula V and the compound represented by formula X were dissolved in THF solvent, the temperature was raised to 50°C, and the reaction was stirred for 24 hours. The solvent was concentrated and passed through a column. The white solid product was collected using an eluent of petroleum ether / ethyl acetate = 3:1. The yield was 58%.

[0038] (b) Trifluoroacetic acid was added to the collected product and stirred at room temperature for 30 minutes. After the reaction was completed, the trifluoroacetic acid was concentrated, and the remaining trifluoroacetic acid was neutralized with a saturated sodium bicarbonate aqueous solution. The reactant was extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent was concentrated and the product was drained. The yield was 90%.

[0039] The structural confirmation data are as follows: 1 H NMR (500 MHz, DMSO- d 6) δ 9.42 (s, 1H), 8.94 (s, 2H), 8.62 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H),7.24 (s, 1H), 7.21 – 7.14 (m, 2H), 5.23 (q, J = 7.9 Hz, 1H), 4.11 – 3.98 (m,2H), 2.92 – 2.66 (m, 2H), 2.33 (s, 4H), 1.80 (dq, J = 12.6, 8.6 Hz, 1H). See Figure 1 .

[0040] 13 C NMR (126 MHz, DMSO- d 6) δ 168.23, 166.36, 154.69, 145.99, 145.09,143.13, 132.62, 129.98, 129.08, 128.74, 126.82, 126.15, 125.03, 53.94, 44.38,33.24, 30.11, 21.61. See Figure 2 .

[0041] Other series of compounds of Formula I can be prepared according to the above method. The numbers, structures, and physical and chemical data of some compounds are shown in Table 1, and the H NMR and mass spectrometry data of the structure identification are shown in Table 2.

[0042] Table 1. Structures and physicochemical properties of some compounds

[0043] Table 2. NMR characterization and high-resolution data of some compounds

[0044] Example 2: Determination of insecticidal activity of the compound represented by formula I Determination method: The test insects were treated with the drip method, and the concentration of the test compound was 500mg / L and 200mg / L. The results were checked after 3 days. If the insects could not crawl normally after touching the body lightly, they were considered dead. The insecticidal activity data of some compounds are shown in the table below.

[0045] The following test targets: diamondback moth, Spodoptera litura, beet armyworm, corn armyworm were purchased from commercial sources. They were fed with corresponding feeds indoors, and the rearing conditions were room temperature (27±1)℃, humidity of 40%, light intensity of 2000lux, and light duration of 12h per day. Under indoor rearing conditions, 3rd instar larvae with the same age, weight and physiological condition were used for the drug activity screening test.

[0046] Table 3. Insecticidal activity of some compounds against Plutella xylostella (500 mg / L, 200 mg / L)

[0047] Table 4. Insecticidal activity of some compounds against Spodoptera exigua (500 mg / L, 200 mg / L)

[0048] Table 5. Insecticidal activity of some compounds against Spodoptera litura (500 mg / L, 200 mg / L)

[0049] Table 6. Insecticidal activity of some compounds against corn armyworm (500 mg / L, 200 mg / L)

[0050] The present invention has been described in detail above. For those skilled in the art, without departing from the purpose and scope of the present invention, and without the need to carry out unnecessary experimental conditions, the present invention can be implemented in a wide range under equivalent parameters, concentrations and conditions. Although the present invention provides specific embodiments, it should be understood that the present invention can be further improved. In a word, according to the principles of the present invention, the application is intended to include any changes, uses or improvements to the present invention, including departure from the disclosed scope in the application, and changes made with conventional techniques known in the art.

Claims

1. Compound represented by formula I: In formula I, R is: -C substituted with 0, 1, 2, 3, 4 or 5 groups selected from the following 1-6 Alkyl or C 3-6 Cycloalkyl: halogen, amino, C 1-6 Alkoxy; C 1-6 alkyl substituted amino; aryl or aryl substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of halogen, nitro, amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-4 A haloalkyl group; wherein The aryl group includes phenyl, naphthyl and furyl.

2. The compound according to claim 1, characterized in that R is one of methyl, ethyl, propylcyclopropane, methylamino, n-propyl, phenyl, m-fluorophenyl, p-methylphenyl, m-methoxyphenyl, p-bromophenyl, m-trifluoromethylphenyl, p-nitrophenyl, m-chlorophenyl, o-chlorophenyl, naphthyl, methoxyethyl, and 2-furan.

3. The compound according to claim 1, characterized in that The compound represented by formula I is selected from any one of the following compounds: 。 4. A method for preparing a compound according to any one of claims 1 to 3, comprising the steps of: (1) 5-chloro-1-indanone represented by formula II undergoes a reductive amination reaction with ammonium acetate in the presence of a reducing agent to obtain a compound represented by formula III; (2) In the presence of a condensing agent and a catalyst, the compound represented by formula III reacts with Boc-glycine to remove Boc to obtain a compound represented by formula V; (3) under alkaline conditions, the isomethylthiourea hemisulfate represented by formula VI reacts with di-tert-butyl dicarbonate represented by formula VII to obtain the mono-Boc-protected isomethylthiourea represented by formula VIII; (4) Under alkaline conditions, the mono-Boc-protected isomethylthiourea reacts with the acyl chloride represented by formula IX to obtain the compound represented by formula X; In formula IX and formula X, R is defined as R in claim 1; (5) Under alkaline conditions, the compound represented by formula V reacts with the compound represented by formula X to remove Boc to obtain the compound represented by formula I.

5. Use of the compound of formula I according to any one of claims 1 to 3 in preventing and controlling agricultural harmful organisms.

6. The use according to claim 5, characterized in that: The application is that the compound represented by formula I is suitable for controlling beet armyworm, diamondback moth, cabbage looper, cutworm, cabbage armyworm, cotton bollworm, tobacco budworm, and leaf roller on crops; Among them, the crops include cabbage, kale, tomato, pepper, cucumber, apple, pear, peach, apricot, cotton, potato, grape, tea and corn.

7. An insecticide, comprising the compound of formula I according to any one of claims 1 to 3 or using the compound of formula I as an active ingredient.

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