CN1326849C - Hexahydro-phthalmide compound, its preparation and use thereof - Google Patents

Abstract

The invention relates to an imide compound and a preparation method thereof, which can be used to prepare a bactericide, which is an imide compound represented by structural formula I and a non-toxic salt thereof: in the inert solvent water, 1,4-diox In the presence of a single solvent or a mixed solvent in hexacyclic, dichloromethane, chloroform, tetrahydrofuran, toluene, and trimethylbenzene, the reaction temperature is kept at 80-150 ° C, and the compound shown in the structural formula II is reacted with the compound shown in the structural formula III to obtain The compound shown in structural formula I, wherein: R ₁ is independently selected from hydroxyl, mercapto, alkyl, SCN, N ₃ , aryl, heteroaryl, fused heteroaryl; R ₂ and R ₃ are independently selected from H atom, hydroxyl, mercapto, halogen, SCN, alkyl, alkoxy, N ₃ , aryl, heteroaryl, fused heteroaryl; X is N atom or CH. The compound of the invention has a reasonable structure and a simple and convenient preparation method, and is used for the preparation of fungicides.

Description

Hexahydrophthalimide compounds and their preparation and use

technical field

The invention relates to an imide compound, especially an imide compound used in the preparation of a fungicide, and a preparation method thereof.

Background technique

There are many reports of imide compounds as bactericides, and some are commercialized, such as: captan (captan), folpet (folpet), tetrachlordane (Captafol), Yipu Tong. (Iprodione) and Vinclozolin, etc.:

But some of these fungicides are not friendly to the environment and have toxic side effects on people. And long-term use will cause the strain to develop obvious resistance. Therefore, designing and synthesizing fungicides with high efficiency, low toxicity, broad spectrum, high selectivity, low residue and low resistance is an urgent problem in the current pesticide research.

Contents of the invention

The invention provides an imide compound, which has bactericidal activity and can be applied to the preparation of bactericides.

The technical solution adopted by the present invention to solve its technical problems is:

The invention provides a kind of imide compound is the compound represented by structural formula (I) and non-toxic salt thereof:

Wherein, R ₁ is independently selected from hydroxyl, mercapto, alkyl, SCN, N ₃ , aryl, heteroaryl, fused heteroaryl; R ₂ and R ₃ are independently selected from H atom, hydroxyl, mercapto, halogen atom, SCN, alkyl, alkoxy, N ₃ , aryl, heteroaryl, fused heteroaryl; X is N atom or CH.

The imide compounds represented by structural formula (I) and their non-toxic salts are selected from:

N-(4,6-bismethylpyrimidin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-1)

N-(4-chloro-6-methylpyrimidin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-2)

N-(4-methylpyrimidin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-3)

N-(6-methylpyridin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-4)

The preparation method of the imide compound represented by structural formula (I): in the presence of a single solvent or a mixed solvent in inert solvent water, 1,4-dioxane, methylene chloride, chloroform, tetrahydrofuran, toluene, trimethylbenzene , the reaction temperature is maintained at 80-150 ° C, the compound shown in the structure (II) is reacted with the compound shown in the structural formula (III), to obtain the compound shown in the structural formula (I),

Wherein: R ₁ is independently selected from hydroxyl, mercapto, alkyl, SCN, N ₃ , aryl, heteroaryl, fused heteroaryl; R ₂ and R ₃ are independently selected from H atom, hydroxyl, mercapto, halogen atom, SCN, alkyl, alkoxy, N ₃ , aryl, heteroaryl, fused heteroaryl; X is N atom or CH.

The pharmaceutically acceptable salts of general formula (I) provided by the present invention also fall within the scope of the present invention.

The compound of the present invention can be a crystalline substance or a solvated substance (such as a hydrate), and the substances in both states are within the scope of the present invention. The solvation method is widely known in the prior art and will not be repeated here. .

Bactericidal activity

In order to clarify the antibacterial spectrum and bacteriostatic activity of this series of compounds to various plant pathogenic bacteria, the inventors carried out indoor bacteriostatic determination of this series of compounds. The method and results are as follows:

The drug-containing medium method is used. Weigh the medicaments with a ten-thousandth balance. Weigh 5 mg of the compound, dissolve it with 0.1 mL of acetone, add Tween 80 to stabilize it, then prepare a dilution solution with a certain concentration of 250 μg/mL with quantitative sterile distilled water, and take 4 mL of the compound dilution solution into a sterilized small Erlenmeyer flask , add 36mL PDA culture medium (the concentration is diluted 10 times accordingly), after mixing evenly, pour it into 3 sterilized plates equally. After the culture medium was solidified, the activated bacteria slices with a diameter d of 5 mm were inserted, and the bacteria slices inoculated with acetone and Tween 80 dilution were used as the blank control. Each treatment was repeated 3 times. After inoculation, put the plate into a constant temperature incubator at 25°C, cultivate for 48 hours, measure the increase in colony radius, and calculate the antibacterial rate (Table 1).

Table 1 Bactericidal activity results

serial number Inhibition rate Cucumber blight cucumber wilt Tomato Botrytis tomato leaf mold Sclerotinia lettuce pepper blight apple ring disease I-1 1 - 2 1 - 1 3 I-2 - - - - - - -

I-3 - - - 1 1 1 2 I-4 3 1 2 3 - 5 3

Note: Inhibition rate = 0-20% is represented by 1; inhibition rate = 20-40% is represented by 2; inhibition rate = 40-60% is represented by 3; inhibition rate = 60-80% is represented by 4; Inhibition rate = 80-100% is represented by 5; - indicates negative inhibition rate or not tested.

In the biological activity test of the above-mentioned test samples, it was found that this type of compound has good bactericidal activity and bactericidal spectrum.

The invention has the beneficial effects of reasonable compound structure, wide range of raw materials, simple preparation method, low synthesis process cost, good bactericidal activity and bactericidal spectrum, and the product meets the requirements of environmental friendliness and green chemistry.

Description of drawings

no drawings

Detailed ways

After a lot of research, the inventors found that the imide compound (I) has good biological activity and can be directly used as a medicine or a fungicide, or as an intermediate of a useful medicine or a fungicide.

Wherein, R ₁ is independently selected from hydroxyl, mercapto, alkyl, SCN, N ₃ , aryl, heteroaryl, fused heteroaryl; R ₂ and R ₃ are independently selected from H atom, hydroxyl, mercapto, halogen atom, SCN, alkyl, alkoxy, N ₃ , aryl, heteroaryl, fused heteroaryl; X is N atom or CH.

In order to achieve the purpose of synthesis, the inventors adopted the method shown in Reaction Scheme 1.

Reaction scheme 1

In Reaction Scheme 1, R ₁ is independently selected from hydroxyl, mercapto, alkyl, SCN, N ₃ , aryl, heteroaryl, fused heteroaryl; R ₂ and R ₃ are independently selected from H atom, hydroxyl , mercapto, halogen atom, SCN, alkyl, alkoxy, N ₃ , aryl, heteroaryl, condensed heteroaryl; X is N atom or CH.

In the reaction scheme 1, the solvent for all reactions can be a single solvent or a mixed solvent in water, 1,4-dioxane, methylene chloride, chloroform, tetrahydrofuran, toluene, and mesitylene, and the reaction temperature is kept at 80°C -150°C.

The present invention will be described in detail through examples below, but the present invention is not limited to these examples, and the reagents not mentioned in the examples are purchased from the market and used as they are.

Example 1: Preparation of N-(4,6-bismethylpyrimidin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-1) Weighing 1, 152 mg (1 mmol) of 2,3,4,5,6-hexahydrophthalic anhydride was placed in a 25 mL round bottom flask, 10 mL of chloroform was added, and 123 mg of 2-amino-4,6-bismethylpyrimidine (1 mmol) was added thereto. The reaction temperature was maintained at 80°C. After stirring for 12 hours, column chromatography (40 g of silica gel H, eluted with 2% CH ₃ OH/CH ₂ Cl ₂ ) after desolventization gave 172 mg of white solid. Yield 62%. Its physical and chemical data are as follows: [ ¹ H]NMR (400MHz, CDCl ₃ ): δ/ppm; 7.055(s, 1H, H-pyrimidine), 3.060-3.037(t, J ₁ =4.381Hz, J ₂ =4.578Hz, 2H, 2CH), 2.517 (s, 6H, 2CH ₃ ), 1.919 (br.m, 4H, 2CH ₂ ), 1.533-1.478 (m, 4H, 2CH ₂ ). Mp. 182-183°C.

Example 2: Preparation of N-(6-methylpyridin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-4) Weigh 3,4,5 152 mg (1 mmol) of 6-tetrahydrophthalic anhydride was placed in a 25 mL round bottom flask, 10 mL of trimethylbenzene was added, and 108 mg of 2-amino-6-methylpyridine (1 mmol) was added thereto. The reaction temperature was maintained at 150°C. After stirring for 10 hours, column chromatography (40 g of silica gel H, eluted with 2% CH ₃ OH/CH ₂ Cl ₂ ) after desolventization gave 177 mg of white solid. Yield 73%. Its physical and chemical data are as follows: [ ¹ H]NMR (400MHz, CDCl ₃ ): δ/ppm; 7.703-7.664(t, J ₁ =7.750Hz, J ₂ =7.731Hz, 1H, Py), 7.172-7.153(d, J=7.667Hz, 1H, Py), 7.018-6.998(d, J=7.787Hz, 1H, Py), 3.033-3.011(m, 2H, 2CH), 2.545(s, 3H, _CH3 ), 1.885(br .s, 4H, 2CH ₂ ), 1.478-1.471 (m, 4H, 2CH ₂ ). Mp. 92-94°C.

Example 3: The reaction temperature was maintained at 110° C., and 10 mL of chloroform was added instead of 10 mL of toluene. The other reaction conditions were the same as in Example 1, the yield was 67%, and the physical and chemical data of the product were the same as in Example 1.

Example 4: The reaction temperature was maintained at 120° C., and 10 mL of trimethylbenzene was added instead of 7 mL of trimethylbenzene and 3 mL of chloroform. The other reaction conditions were the same as in Example 2, the yield was 75%, and the physical and chemical data were the same as in Example 2.

Compound (I) can be prepared by changing the type of compound (II) according to Example 1. When (II) is 2-amino-4-chloro-6-methylpyrimidine, N-(4-chloro-6-methylpyrimidin-2-yl)-1,2,3,4,5,6- Hexahydrophthalimide (I-2); When (II) is 2-amino-4-methylpyrimidine, generate N-(4-methylpyrimidin-2-yl)-1,2,3,4, 5,6-Hexahydrophthalimide (I-3). Physicochemical data of other compounds:

N-(4-chloro-6-methylpyrimidin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-2) white solid. [ ¹ H]NMR ( 400MHz, CDCl ₃ ): δ/ppm; 7.247(s, 1H, pyrimidine), 3.055-3.033(m, 2H, 2CH), 2.555(s, 3H, CH ₃ ), 1.894(br.s, 4H, 2CH ₂ ), 1.490-1.478 (m, 4H, 2CH ₂ ). Yield = 50%. Mp. 100-107°C.

N-(4-methylpyrimidin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-3) white solid [ ¹ H]NMR (400MHz, CDCl ₃ ) : δ/ppm; 8.686-8.673 (d, J=5.073Hz, 1H, pyrimidine), 7.203-7.191 (d, J=5.093Hz, 1H, pyrimidine), 3.072--3.050m, 2H, 2CH), 2.579 ( s, 3H, CH ₃ ), 1.913 (br.s, 4H, 2CH ₂ ), 1.503--1.451 (m, 4H, 2CH ₂ ). Yield = 48%. Mp. 176-178°C.

The above are only preferred embodiments of the present invention, and are not intended to limit the present invention in any form. Any simple modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present invention still belong to the present invention. within the scope of the technical solution of the invention.

Claims (4)

1. An imide compound, characterized in that: its structure is a compound represented by structural formula I: Wherein, R ₁ is independently selected from an alkyl group; R ₂ is independently selected from an H atom; R ₃ is independently selected from a halogen atom and an alkyl group; X is an N atom or CH. 2. An imide compound according to claim 1, characterized in that: the compound represented by the structural formula I is selected from: N-(4,6-bismethylpyrimidin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-1) N-(4-chloro-6-methylpyrimidin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-2) N-(4-methylpyrimidin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-3) N-(6-methylpyridin-2-yl)-1,2,3,4,5,6-hexahydrophthalimide (I-4). 3. The preparation method of a kind of imide compound according to claim 1, characterized in that: in the inert solvent water, 1,4-dioxane, dichloromethane, chloroform, tetrahydrofuran, toluene, trimethylbenzene In the presence of a single solvent or a mixed solvent, the reaction temperature is kept at 80°C-150°C, and the compound shown in the structure II is reacted with the compound shown in the structure formula III to obtain the compound shown in the structure formula I, Wherein: R ₁ is independently selected from an alkyl group; R ₂ is independently selected from an H atom; R ₃ is independently selected from a halogen atom and an alkyl group; X is an N atom or CH. 4. The use of an imide compound according to claim 1, characterized in that it is used in the preparation of plant fungicides.