5-chloroindane compounds containing guanidino groups, processes for their preparation and use

Abstract

The application discloses a 5-chloroindane compound containing a guanidyl group and a preparation method and application thereof. A structural formula of the compound is shown as formula I. The application designs and synthesizes a novel compound containing a 5-chloroindane and a guanidyl active fragment, and activity determination results show that the compound has high insecticidal activity on insects such as Plutella xylostella. The application has important significance for the prevention and treatment of diseases and pests in agriculture, and can provide a new and efficient control means for agricultural production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of new pesticide creation, and particularly relates to a 5-chloroindane compound containing a guanidine group and a preparation method and application thereof. BACKGROUND

[0002] Agriculture is the basis of human survival and development, and pesticides, as an important part of agricultural production, play a key role in improving 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, and so on, which restrict the further application and development of pesticides. Therefore, it is of great significance to create new insecticides and delay the development of resistance to commercial insecticides. Indoxacarb is a highly effective insecticide developed by Dupont Company in the United States, which 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 drug resistance and environmental pollution have become increasingly prominent. SUMMARY

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

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

[0005]

[0006] In formula I, R can be: -C selected from 0, 1, 2, 3, 4 or 5 groups substituted by 1-6 alkyl or C 3-6 cycloalkyl: halogen, amino, C 1-6 alkoxy; C 1-6 alkyl-substituted amino; or aryl or 0, 1, 2, 3, 4 or 5 groups substituted by aryl selected from the group consisting of halogen, nitro, amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-4 haloalkyl; wherein the aryl includes phenyl, naphthyl, furanyl;

[0007] 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.

[0008] In some embodiments of the present application, the compound shown in formula I is selected from any one of the following compounds:

[0009]

[0010] The compound of formula I is prepared by the following method:

[0011] (1) 5-chloro-1-indanone of formula II is subjected to reductive amination in the presence of ammonium acetate and a reducing agent to obtain a compound of formula III;

[0012]

[0013] (2) the compound of formula III is subjected to reaction with Boc-glycine in the presence of a condensing agent and a catalyst, and Boc is removed to obtain a compound of formula V;

[0014]

[0015] (3) isomethylthiourea hemisulfate of formula VI is subjected to reaction with di-tert-butyl dicarbonate of formula VII in the presence of a base to obtain a single Boc-protected isomethylthiourea of formula VIII;

[0016]

[0017] (4) the single Boc-protected isomethylthiourea is subjected to reaction with an acyl chloride of formula IX in the presence of a base to obtain a compound of formula X;

[0018]

[0019] In formula IX and formula X, R is as defined above;

[0020] (5) the compound of formula V is subjected to reaction with the compound of formula X in the presence of a base, and Boc is removed to obtain the compound of formula I.

[0021] In step (1) of the above method, the reducing agent is sodium cyanoborohydride,

[0022] The reaction is carried out in an organic solvent, and the organic solvent can be isopropyl alcohol in particular.

[0023] After the reaction is completed, the reaction solution needs to be quenched with sodium hydroxide aqueous solution.

[0024] In step (2), the condensing agent is EDCI or DCC, and the catalyst is DMAP;

[0025] The reaction is carried out in an organic solvent, and the organic solvent can be dichloromethane in particular.

[0026] 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 1:1-5:1, and the two solvents are dioxane / water, tetrahydrofuran / water or acetone / water.

[0027] The base used is any one of sodium bicarbonate, sodium carbonate, potassium carbonate or sodium hydroxide.

[0028] In step (4), the reaction temperature is 0-25℃, and the reaction is carried out in a solvent, and the solvent used is dichloromethane, toluene, DMF or acetone; the base used can be any one of triethylamine, 4-DMAP and potassium carbonate.

[0029] In step (5), the reaction is carried out in a solvent, and the solvent used is DMF, dioxane or tetrahydrofuran, and the reaction temperature is 25-70℃.

[0030] The second object of the present application is to provide the use of the compound of formula I in the control of agricultural pests.

[0031] The use is that the compound of formula I is suitable for controlling Spodoptera exigua, Plutella xylostella, Pieris rapae, Spodoptera litura, Mamestra brassicae, Helicoverpa armigera, Heliothis assulta, and the like on crops.

[0032] The crops include Brassica oleracea, Brassica rapa, tomato, pepper, cucumber, apple, pear, peach, apricot, cotton, potato, grape, tea and corn.

[0033] The present application also provides an insecticide containing the compound of formula I or the compound of formula I as an active ingredient.

[0034] The present application designs and synthesizes a novel compound containing 5-chloroindan and guanidyl active fragments, and the activity determination result shows that the compound has high insecticidal activity on insects such as Plutella xylostella. The present application has important significance for the control of pests in agriculture, and can provide a new and efficient control method for agricultural production. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 The compound prepared in Example 1 of the present application is subjected to nuclear magnetic resonance hydrogen spectrum.

[0036] Figure 2 The compound prepared in Example 1 of the present application is subjected to nuclear magnetic resonance hydrogen spectrum. DETAILED DESCRIPTION

[0037] The present application is further described in detail below in combination with specific embodiments, and the examples given are only for illustrating the present application, and are not intended to limit the scope of the present application. The examples provided below can serve as a guide for further improvement by those skilled in the art, and do not constitute any limitation on the present application in any way.

[0038] The experimental methods in the following examples are all conventional methods, unless otherwise specified, and are performed according to the techniques or conditions described in the literature in the art or according to the instructions of the products. The materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained commercially.

[0039] Example 1, Preparation of Compound A4

[0040]

[0041] 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 isopropyl alcohol to the round-bottom flask, 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 isopropyl alcohol, then extract the reaction liquid with ethyl acetate, collect the organic phase, dry with anhydrous sodium sulfate, concentrate the solvent, and then pass through a column, using petroleum ether / ethyl acetate = 1:1 as eluent to collect the yellow oily product III, with a yield of 48%.

[0042] The structure 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).

[0043] 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.

[0044]

[0045] (a) Take 1 mmol of the compound shown in formula III and put it into a 100 ml round bottom flask, add dichloromethane to stir and dissolve, then add 1.2 eq of the compound shown in formula IV and 1.5 eq of EDCI, stir for a period of time, then add 0.1 eq of DMAP to the solution. Stir the reaction at room temperature for 3 hours, then wash with deionized water, saturated brine, collect the organic phase, dry with anhydrous sodium sulfate, concentrate the solvent, then pass through a column, use petroleum ether / ethyl acetate = 3:1 eluent to collect the white solid product.

[0046] (b) Add trifluoroacetic acid to the collected product, stir at room temperature for 30 minutes, after the reaction is completed, concentrate the trifluoroacetic acid, neutralize the remaining trifluoroacetic acid with saturated aqueous sodium bicarbonate solution, extract the reaction with dichloromethane, dry with anhydrous sodium sulfate, concentrate the solvent, and dry the product (compound shown in formula V), with a yield of 85%.

[0047] Structural confirmation data is 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).

[0048] 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.

[0049]

[0050] Dissolve 0.15 mol of isomethylthiourea hemisulfate shown in formula VI and 0.15 mol of sodium bicarbonate in 40 ml of solvent (V THF :V H2O=1:1) in ice water bath and slowly drop 0.1 mol of Boc anhydride of formula VII into the flask, drop 20 min, continue to stir at room temperature for 1 hour, after the reaction is completed, remove THF by concentration, extract the residue with dichloromethane, collect the dichloromethane phase, dry with anhydrous sodium sulfate, concentrate the solvent, and then pass through a column to collect the white solid product VIII with a yield of 69%.

[0051] The structure confirmation data are as follows: 1 H NMR (500 MHz, Chloroform- d ) δ 2.39 (s, 3H), 1.44(s, 9H).

[0052] 13 C NMR (126 MHz, Chloroform- d ) δ 171.9, 160.6, 79.1,27.6,12.7.

[0053]

[0054] Dissolve 0.1 mol of Boc anhydride-protected isomethylthiourea of formula VIII in 40 ml of dichloromethane, and slowly drop 0.2 mol of p-methyl benzoyl chloride-dichloromethane solution into the flask under ice water stirring, continue to stir after drop, and add water to extract the reaction solution after monitoring the end of the reaction by spotting, collect the dichloromethane phase, dry with anhydrous sodium sulfate, concentrate the solvent, pass through a column, collect the white solid product using petroleum ether / ethyl acetate = 100:1 as an eluent, and the yield is 80%.

[0055] The structure 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).

[0056] 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.

[0057]

[0058] (a) 1.5 mmol of the compound shown in formula V was dissolved in solvent THF, and warmed to 50°C, and stirred for 24 hours. The solvent was concentrated and the product was collected by column using petroleum ether / ethyl acetate = 3:1 as eluent, and the white solid product was obtained with a yield of 58%.

[0059] (b) The collected product was added into trifluoroacetic acid, 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 saturated aqueous sodium bicarbonate solution. The reaction was extracted with dichloromethane, dried with anhydrous sodium sulfate, and the solvent was concentrated. The product was dried under vacuum, and obtained with a yield of 90%.

[0060] The structure 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 .

[0061] 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 .

[0062] Other series of compounds of general formula I can be prepared according to the above method. The compound numbers, structures, and physicochemical data of some compounds are shown in Table 1, and the structure-identified nuclear magnetic resonance hydrogen spectrum and mass spectrum data are shown in Table 2.

[0063] Table 1. Structures of some compounds and their physicochemical properties

[0064]

[0065] Table 2. NMR characterization and high resolution data of some compounds

[0066]

[0067] Example 2. Determination of insecticidal activity of compounds of formula I

[0068] Method of determination: The insects to be tested were treated by spot-on method, and the concentration of the compounds to be tested was 500 mg / L and 200 mg / L. The results were checked after 3 days. The individuals that could not crawl normally were considered dead by light touch. The insecticidal activity data of some compounds are shown in the following table.

[0069] The following test targets: Plutella xylostella, Helicoverpa armigera, Spodoptera exigua, Ostrinia nubilalis were purchased from commercial channels. They were fed with corresponding feed in the laboratory, and the feeding conditions were room temperature (27±1) °C, humidity 40%, light intensity 2000 lux, and light time 12 h per day. Under the indoor feeding conditions, 3rd instar larvae with uniform instar, body weight and physiological condition were used for pesticide activity screening test.

[0070] Table 3. Insecticidal activity of some compounds against Plutella xylostella (500 mg / L, 200 mg / L)

[0071]

[0072] Table 4. Insecticidal activity of some compounds against Spodoptera exigua (500 mg / L, 200 mg / L)

[0073]

[0074] Table 5. Insecticidal activity of some compounds against Helicoverpa armigera (500 mg / L, 200 mg / L)

[0075]

[0076] Table 6. Insecticidal activity of some compounds against Ostrinia nubilalis (500 mg / L, 200 mg / L)

[0077]

[0078] The application has been described in detail. For those skilled in the art, the application can be implemented in a wider range under the same parameters, concentrations and conditions without departing from the spirit and scope of the application and without unnecessary experiments. Although the application gives a special example, it should be understood that the application can be further improved. In summary, according to the principle of the application, the application intends to include any change, use or improvement of the application, including the change made by the conventional technology known in the art, which is out of the range disclosed in the application.

Claims

1. A compound of formula I: ###0001### wherein R is one of methyl, ethyl, propyl, methylamino, meta-fluorophenyl, para-methylphenyl, para-bromophenyl, meta-chlorophenyl, ortho-chlorophenyl. In formula I, R is alkyl, alkyl, any one of alkyl.

2. The compound of claim 1, wherein The compound of formula I is selected from any one of the following compounds: ###0002### ###0003### ###0004### ###0005### ###0006### 3. The compound of claim 1, wherein 4. A method for preparing the compound of any one of claims 1 to 3, comprising the following steps: (1) 5-chloro-1-indanone of formula II is subjected to reductive amination with ammonium acetate in the presence of a reducing agent to obtain a compound of formula III; ###0007### (2) the compound of formula III is reacted with Boc-glycine in the presence of a condensing agent and a catalyst, and the Boc group is removed to obtain a compound of formula V; ###0008### (3) under basic conditions, isomethylthiourea hemisulfate of formula VI is reacted with di-tert-butyl dicarbonate of formula VII to obtain mono-Boc protected isomethylthiourea of formula VIII; ###0009### (4) under basic conditions, mono-Boc protected isomethylthiourea is reacted with acyl chloride of formula IX to obtain a compound of formula X; ###0010### wherein R is defined as in claim 1; (5) under basic conditions, the compound of formula V is reacted with the compound of formula X, and the Boc group is removed to obtain the compound of formula I. 。 5. Use of the compound of formula I of any one of claims 1 to 3 for controlling agricultural pests. The use is that the compound of formula I is suitable for controlling Spodoptera exigua, Plutella xylostella, Pieris rapae, Spodoptera litura, Mamestra brassicae, Helicoverpa armigera, Mamestra oleracea, and the like on crops. The crops are selected from Brassica oleracea, Brassica rapa, Solanum lycopersicum, Capsicum annuum, Cucumis sativus, Malus domestica, Pyrus pyrifolia, Prunus persica, Prunus armeniaca, Gossypium hirsutum, Solanum tuberosum, Vitis vinifera, Camellia sinensis, and Zea mays.

7. An insecticide comprising the compound of formula I of any one of claims 1 to 3 or taking the compound of formula I as an active ingredient. ​ ​ ​ ​ 6. Use according to claim 5, characterized in that, ​ ​ ​

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