CN105439979B - Benzoyl hydazone derivative containing 1,2,3 thiadiazoles and preparation method and application - Google Patents

Abstract

The invention belongs to the field of organic compound synthesis, and specifically relates to benzoylhydrazone derivatives containing 1,2,3-thiadiazole, a preparation method and application thereof. The structure of this type of compound is shown in formula I. In the present invention, the synthesis method of the compound of formula I is simple to operate, easy to obtain raw materials, does not produce harmful by-products, and has a high yield. The biological activity test found that the compound represented by formula I exhibited excellent fungicidal activity, and could be used in agricultural production to prevent and control apple rot, rice sheath blight, melon and fruit rot, tomato gray mold, and tomato early blight and rice bakanae disease, and has good application and development value.

Description

Benzoylhydrazone Derivative Containing 1,2,3-Thiadiazole and Its Preparation Method and Application

technical field

The invention belongs to the field of organic chemical synthesis, and in particular relates to a benzoylhydrazone derivative containing 1,2,3-thiadiazole, a preparation method thereof, and an application of the compound in sterilization.

Background technique

Heterocyclic compounds have become the mainstream field of research and development of new pesticides, and nitrogen-containing heterocycles are the focus of research. According to statistics, about 70% of ultra-efficient pesticides are nitrogen-containing heterocycles (Chen, Q. et. al. Eur. J. Med. Chem. 2008, 43, 595.). Among them, 1,2,3-thiadiazole has a unique structure, good environmental compatibility and a wide range of biological activities, and is more and more favored by researchers, and reports on its biological activities are increasing day by day. 1,2,3-Thiadiazole derivatives have bactericidal, herbicidal, insecticidal, anti-cancer, and disease-resistant activities (Zuo, X.et.al.J.Agric.Food.Chem.2010,58,2755.; Tripathy, R.et.al.Bioorg.Med.Chem.Lett.2007,17,1793.; Fan, Z-J.et.al.J.Agric.FoodChem.2009,57,4279.), many researchers are This is a more in-depth study.

There have been many reports on the biological activity of salicylic acid and its derivatives. Miyazawa reported that it can induce resistance to Fusarium wilt in tomatoes; Nasser Yalpani reported that it can induce tobacco resistance to TMV; Katsumichi reported that it can induce resistance to rice blast , grape downy mildew, tomato and potato late blight, and rust have good antibacterial effects (Nasser Yalpani, et. al. The Plant Cell. 2001.; Miyazawa. Physiol Mol Plant P. 1988.; Aoki, Katsumichi. UK Pat .Appl.1979.).

Acylhydrazone compounds, as a special class of Shiff bases, contain a good active group (CONHN=CH), have unique and excellent biological activity and strong coordination ability (Syarmal, A.et.al.Chem. Rev.1989,9(2):183-185), has been the subject of extensive research in pesticides, medicines and analytical reagents (Wang Jianping, Organic Chemistry, 2007,27(4):524-529; Li Qinghan et al., Chemical Research and Application, 2008,20(8):988-991.). Acylhydrazone compounds have been widely used in treating tuberculosis, scavenging O ^2- free radicals in organisms and inhibiting bacteria (NAM, N H.etal.J.Chem.Soc.1953,(3):1358-1364.) . However, there are few research literatures on acylhydrazone derivatives containing thiadiazole rings.

In order to obtain a new type of drug molecule with excellent biological activity, according to the active substructure splicing design principle of the drug, the 1,2,3-thiadiazole molecule and the salicylic acid derivative were connected together through an acylhydrazone bond, and the compound was designed and synthesized. Benzoylhydrazone derivatives containing 1,2,3-thiadiazole were screened for bactericidal biological activity in order to provide candidate compounds for the creation of new pesticides.

Contents of the invention

The object of the present invention is to provide benzoylhydrazone derivatives containing 1,2,3-thiadiazole, a preparation method thereof and an application in preventing and controlling agricultural diseases. The specific technical scheme is as follows:

Benzoylhydrazone derivatives containing 1,2,3-thiadiazole, the general formula of the derivatives is formula I:

Wherein R ₁ is H, C ₁ ~C ₁₀ alkyl, haloalkyl, phenyl, benzyl, halogen, nitro, thiazole or pyridine; R ₂ is a single or disubstituted group on the benzene ring, so Such groups include H, alkyl, halogen, alkoxy, epoxy, naphthyl, nitro or trifluoromethyl.

Further, the R ₁ is bromine, chlorine, fluorine, methyl, ethyl, propyl or n-butyl; R ₂ is a single substituent group or a disubstituted group, and the group includes fluorine, chlorine, bromine or trifluoromethyl.

The preparation method of the above-mentioned benzoylhydrazone derivative containing 1,2,3-thiadiazole comprises the following steps:

Add the compound shown in formula II to organic solvent A and stir, then add an acidic substance to activate, then dissolve the compound shown in formula III in organic solvent A, and slowly add to the reaction system; after the reaction is completed, recrystallize or filter with suction to obtain Compound shown in formula I;

Reaction a:

The organic solvent A includes aliphatic, alicyclic or aromatic hydrocarbons or their halogenated products: benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, methylene chloride , chloroform or carbon tetrachloride; ethers: diethyl ether, diisopropyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethylene glycol Alcohol dimethyl ether or ethylene glycol diethyl ether; Ketones: acetone, butanone or methyl isobutyl ketone; Nitriles: acetonitrile, propionitrile or butyronitrile; Amides: such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; esters: such as methyl acetate or ethyl acetate; sulfoxides: di Methyl sulfoxide; alcohols: one or any combination of methanol, ethanol, n-propanol or isopropanol.

The organic solvent is preferably one or any combination of more than one of dichloromethane, acetonitrile, petroleum ether, methanol, ethanol and tetrahydrofuran.

The acidic compound is selected from hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, ferric chloride, stannous chloride, tin tetrachloride, aluminum trichloride, zinc chloride, copper sulfate, ferric sulfate, ferric ammonium sulfate, At least one of ceric sulfate, zirconium tetrachloride and sodium bisulfate, preferably at least one of formic acid and acetic acid, more preferably acetic acid.

The reaction temperature is -20-100°C, preferably 20-80°C, and the reaction time is 1-20h, preferably 3-8h.

The mass ratio of the compound shown in formula II to the compound shown in formula III is 1: (0.8 ~ 1.6), preferably 1: 0.8 ~ 1.0; the amount of the organic solvent is 15-60 times the amount of the compound shown in formula II, Preferably 25-30 times.

Among them, 4-R ₁ -1,2,3-thiadiazole-5-carbaldehyde shown in formula II is prepared by the method shown in reaction formula b:

Reaction b:

Take a certain amount of ethyl 4-R ₁ -1,2,3-thiadiazole-5-carboxylate (Formula IV) and dissolve it in ethanol, slowly add an appropriate amount of NaBH ₄ , after the reaction is completed, the alkali solution quenches the reaction, and extracts it with an organic solvent , the solvent was distilled off under reduced pressure to obtain 4-R ₁ -1,2,3-thiadiazole-5-methanol (compound represented by formula V).

Dissolve the compound represented by formula V in an appropriate amount of dichloromethane, then add PCC, react for a period of time, filter, and remove the solvent from the filtrate by rotary evaporation to obtain the compound represented by formula II.

Among them, ethyl 4-R ₁ -1,2,3-thiadiazole-5-carboxylate (Formula IV) was obtained by reference method (Wang Shouxin, Organic Chemistry, 2013, 33, 2367-2375.).

The substituted benzohydrazide shown in formula (III) is prepared by the following method: substituted ethyl benzoate and hydrazine hydrate are put into the reaction according to the ratio of substances of 1:1 to 1.5, and reflux reaction in ethanol for 3-12 hours, and the reaction After the end, let stand overnight, filter with suction, and dry the filter cake to obtain substituted benzoylhydrazine.

The substituted ethyl benzoate is obtained through the esterification reaction of various substituted benzoic acids in ethanol.

A drug containing the above-mentioned benzoylhydrazone derivatives containing 1,2,3-thiadiazole as an active ingredient.

The above-mentioned benzoylhydrazone derivatives containing 1,2,3-thiadiazole are used as fungicides on crops.

The bacteria controlled by the fungicide are apple rot fungus, rice sheath blight fungus, melon and fruit rot fungus, tomato botrytis cinerea, tomato early blight fungus or rice bakanae fungus.

When needed, one or more acceptable carriers in pesticide formulations can also be added to the drug, and the carriers include conventional diluents, excipients, fillers, binders, lubricants, etc. in pesticide formulations. Wetting agents, absorption enhancers, surfactants, lubricants, stabilizers, defoamers, diatomaceous earth, etc. The dosage form of the prepared medicine is also various, which can be powder, emulsion, liquid, granule, corrosion inhibitor, effervescent tablet and so on.

The beneficial effects of the present invention are:

(1) The preparation method of the present invention is simple and easy, the product is easy to purify, the cost is low, and the yield is high.

(2) The benzoylhydrazone derivatives containing 1,2,3-thiadiazole of the present invention are tested against apple rot fungus, rice sheath blight fungus, melon and fruit rot fungus, tomato gray mold fungus, tomato early blight Bacteria and rice bakanae have high inhibitory activity, and can be used as fungicides in agriculture.

detailed description

The substantive features of the present invention can be realized from the following examples, but it should not be regarded as limiting the present invention in any way. The methods in the following examples are conventional methods unless otherwise specified. The materials, unless otherwise specified, can be obtained from open commercial channels.

Example 1: Preparation and structure identification of 4-butyl-1,2,3-thiadiazole-5-methanol (V-05)

Weigh 8.56g (0.04mol) of ethyl 4-butyl-1,2,3-thiadiazole-5-carboxylate into a 100ml three-neck flask, add 30mL of ethanol to dissolve, then place in an ice-salt bath and cool to 0°C Next, slowly add 2.28g (0.06mol) sodium borohydride, remove the ice-salt bath and heat up to 25°C, react at room temperature for 5 hours, add dilute hydrochloric acid to the reaction system until the solution is acidic, extract with dichloromethane, and use Wash with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to obtain 6.31 g of yellow liquid, which is the intermediate V-05 of the present invention, with a yield of 91.7%.

V-01~V-04 were successfully prepared according to the same method as that used to prepare compound V-05. The physical and chemical data and structural identification data are shown in Table 1. From the relevant data in Table 1, it can be seen that the above products V-01~V-05 The structures are correct, and they are all compounds shown in the general formula of the formula V structure.

Example 2: Preparation and structure identification of intermediate 4-butyl-1,2,3-thiadiazole-5-carbaldehyde (II-05)

Weigh 10.63g (0.05mol) of PCC into a 100ml three-neck flask, add 40ml of dichloromethane and stir to dissolve, then slowly add 6.02g (0.035mol) of 4-butyl-1,2,3-thiadiazole-5-methanol The dichloromethane solution was monitored by TLC until the reaction was complete. Stop the reaction, filter with suction, wash the filtrate with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dry the organic phase with anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to obtain 5.39 g of yellow liquid, which is intermediate II of the present invention -05, yield 90.6%.

According to the same method as the preparation of compound II-05, II-01~II-04 were successfully prepared, and their physical and chemical data and structural identification data are shown in Table 1. From the relevant data in Table 1, it can be known that the above products II-01~II-05 The structures are correct, and they are all compounds shown in the general formula II structure.

Table 1 Physicochemical data and structural identification data of intermediates V and II

Example 3: Preparation and structure identification of 4-methyl-1,2,3-thiadiazole-5-carbaldehyde-2-bromo-benzoylhydrazone (No. I-01)

Add 20mL of methanol and 0.32g (2.5mmol) of the compound 4-methyl-1,2,3-thiadiazole-5-carbaldehyde shown in formula II to a 50mL three-necked flask, stir, and add 0.6mg (0.01mmol) in one go Acetic acid was activated, and then 0.43g (2mmol) of the compound represented by formula III (R2 is bromine substituted at the ₂ -position) 2-bromo-benzohydrazide was dissolved in methanol, slowly added to the above-mentioned three-necked flask, and heated to 78°C under reflux After reacting for 6 hours, stop the reaction. The solvent was removed by rotary evaporation to obtain a crude product, which was recrystallized from ethanol to obtain 0.56 g of a white solid with a yield of 87%. The appearance and melting point of the white solid product are shown in Table 2, and its ¹ H NMR spectrum data are shown in Table 3. It can be seen from Table 3 that the product has a correct structure and is a compound shown in Formula I, numbered I-01.

According to the same method as the preparation of compound I-01, I-02~I-25 were successfully prepared. The physical and chemical data are shown in Table 2, and the structural identification data are shown in Table 3. From the relevant data in Table 3, it can be seen that the above-mentioned products I-01 The structures of ~I-25 are correct, and they are all compounds shown in the general structure of formula I, wherein the R groups are listed in Table 2.

Example 4: Preparation and structural identification of 4-propyl-1,2,3-thiadiazole-5-carbaldehyde-3-trifluoromethyl-benzoylhydrazone (No. I-31)

Add 20 mL of ethanol and 0.47 g (3 mmol) of compound 4-propyl-1,2,3-thiadiazole-5-carbaldehyde shown in formula II to a 50 mL three-necked flask, stir, and add 0.6 mg (0.01 mmol) of acetic acid in one go Activation is carried out, then the compound shown in 0.62g (3mmol) formula III (R ₂ is trifluoromethyl substituted at the 3 position) 3-trifluoromethyl-benzohydrazide is dissolved in ethanol, slowly added in the above-mentioned three-necked flask, After condensation reaction at room temperature for 4 hours, stop the reaction. The reaction solution was placed in the refrigerator overnight, filtered with suction, and the filter cake was dried to obtain 0.81 g of a yellow solid, with a yield of 79%. The appearance and melting point of the white solid product are shown in Table 2, and its ¹ H NMR spectrum data are shown in Table 3. It can be seen from Table 3 that the product has a correct structure and is a compound shown in formula I, numbered I-31.

According to the same method as the preparation of compound I-31, I-26~I-51 were successfully prepared. The physical and chemical data are shown in Table 2, and the structural identification data are shown in Table 3. From the relevant data in Table 3, it can be seen that the above-mentioned products I-26 The structures of ~I-51 are correct, and they are all compounds shown in the general structure of formula I, wherein the R groups are listed in Table 2.

The physicochemical data of table 2 target compound (formula I)

[1] I-03 and I-06 replace R with the structural formula.

The nuclear magnetic data of table 3 target compound (formula I)

Embodiment 5: Bactericidal activity of some compounds of the present invention

The fungicidal activity of the target compounds was determined by the mycelial growth rate method.

The tested bacteria were apple rot fungus, rice sheath blight fungus, melon and fruit rot fungus, tomato cinerea, tomato early blight fungus and rice bakanae fungus, etc.

Weigh 50mg of the target compound respectively, then dissolve the sample in dimethyl sulfoxide, and dilute to a concentration of 5000mg/L respectively for later use.

Take 2mL of the drug solution with a concentration of 5000mg/L and mix it with 98mL of melted potato dextrose agar (PDA) medium to prepare 100mL of a toxic medium with a concentration of 50mg/L. Divide the toxic culture medium into 4 parts equally, and pour them into 4 petri dishes with a diameter of 9 cm respectively to make a toxic PDA plate. After the toxic culture medium in the dish condenses, insert the cultured pathogenic bacteria cake with a diameter of 0.5 cm. Placed in a 25°C incubator. Difenoconazole at the same concentration was used as the control drug, dimethyl sulfoxide was used as the solvent control, and sterile water was used as the blank control. Each sample was repeated 4 times, and the above operations were performed aseptically. After the colonies in the blank control had grown sufficiently, the colony diameters of each treatment were measured by the cross method, and the average value was taken.

Calculated based on the corrected average diameter of blank control and treated colonies

Inhibition rate = (control colony diameter - treated colony diameter) / control colony diameter * 100

The results of the bactericidal activity test are shown in Table 4.

Table 4 formula I compound bactericidal activity

The results in table 4 show that the compounds of the present invention have obvious bactericidal activity, especially compounds containing halogen substituent groups such as I-18, I-26, I-27, I-35, I-37, I-42, I -47 has more obvious bactericidal activity, especially against apple rot fungus and tomato cinerea, such as I-35, I-37, I-42, and I-47 for apple rot fungus 100%) is equivalent to the reference agent difenoconazole (100%), but better than the reference agent thiazilamide (95%); The activity of mold fungus (respectively 85%, 85%, 85%, 83%) is better than that of the control drug thiazil (81%), which has the value of further research as a fungicide.

Claims (11)

1. Containing the benzoylhydrazone derivative of 1,2,3-thiadiazole, it is characterized in that, the general formula of described derivative is formula I: Wherein R ₁ is H, C ₁ ~C ₁₀ alkyl, haloalkyl, phenyl, benzyl, halogen, nitro, thiazole or pyridine; R ₂ is a single or disubstituted group on the benzene ring, so Such groups include H, alkyl, halogen, alkoxy, epoxy, naphthyl, nitro or trifluoromethyl. 2. the benzoylhydrazone derivative containing 1,2,3-thiadiazole according to claim ₁ , is characterized in that, described R is bromine, chlorine, fluorine, methyl, ethyl, propyl group Or n-butyl; R ₂ is a monosubstituted group or a disubstituted group, and the group includes fluorine, chlorine, bromine or trifluoromethyl. 3. the preparation method of the benzoylhydrazone derivative containing 1,2,3-thiadiazole according to claim 1 and 2, is characterized in that, comprises the following steps: Add the compound shown in formula II into organic solvent A and stir, then add acidic substances to activate, then dissolve the compound shown in formula III in organic solvent A, and slowly add to the reaction system; after the reaction is completed, recrystallization or suction filtration, Obtain the compound shown in formula I; The reaction formula is: 4. The preparation method according to claim 3, characterized in that, the organic solvent A is aliphatic or aromatic hydrocarbon or its halogenated product, ethers, ketones, nitriles, amides, esters, One or more of sulfoxides and alcohols. 5. preparation method according to claim 4 is characterized in that, described aliphatic or aromatic hydrocarbon or its halides are benzene, toluene, xylene, chlorobenzene, dichlorobenzene, sherwood oil, hexane, Cyclohexane, methylene chloride, chloroform or carbon tetrachloride; The ethers are diethyl ether, diisopropyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethylene glycol dimethyl ether or ether Glycol diethyl ether; The ketones are acetone, butanone or methyl isobutyl ketone; Described nitriles are acetonitrile, propionitrile or butyronitrile; The amides are N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; The esters are methyl acetate or ethyl acetate; The sulfoxides are dimethyl sulfoxide; The alcohols are one or more of methanol, ethanol, n-propanol or isopropanol. 6. The method according to claim 3, wherein the acidic compound is selected from hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, ferric chloride, stannous chloride, tin tetrachloride, aluminum trichloride , zinc chloride, copper sulfate, ferric sulfate, ferric ammonium sulfate, ceric sulfate, zirconium tetrachloride and sodium bisulfate at least one. 7. The preparation method according to claim 3, characterized in that, the reaction temperature is -20-100°C, and the reaction time is 1-20h. 8. The preparation method according to claim 3, wherein the mass ratio of the compound shown in the formula II to the compound shown in the formula III is 1:(0.8～1.6), and the consumption of the organic solvent is the formula II Show 15-60 times of compound consumption. 9. The medicine that takes the benzoylhydrazone derivative containing 1,2,3-thiadiazole as claimed in claim 1 as an active ingredient. 10. The application of the benzoylhydrazone derivative containing 1,2,3-thiadiazole as a fungicide on crops according to claim 1. 11. The application according to claim 10, characterized in that the germs controlled by the fungicide are apple rot fungus, rice sheath blight fungus, melon and fruit rot fungus, tomato gray mold fungus, tomato early blight fungus or rice rot fungus. Seedling germs.