CN112442024A - 3, 4-dichloroisothiazole amide compound containing 1,2, 4-oxadiazole ring and preparation method and application thereof - Google Patents
3, 4-dichloroisothiazole amide compound containing 1,2, 4-oxadiazole ring and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
The invention relates to a 3, 4-dichloroisothiazole amide compound containing a 1,2, 4-oxadiazole ring, a preparation method and application thereof, wherein the compound has a structure shown in a formula III; the preparation method comprises the following steps: (1)3, 4-dichloroisothiazole-5-formic acid reacts with cyano-substituted aniline or benzylamine to obtain an intermediate I; (2) reacting the intermediate I with hydroxylamine hydrochloride to obtain an intermediate II; (3) reacting the intermediate II with a compound shown as a formula A to obtain a compound shown as a formula III; the bactericide contains the 3, 4-dichloroisothiazole amide compound containing 1,2, 4-oxadiazole ring provided by the invention; the compound or the bactericide is applied to germ inhibition or disease control, and has higher biological activity on agricultural diseases and insect pests.
Description
Technical Field
The invention belongs to the technical field of agricultural disease control, and relates to a 3, 4-dichloroisothiazole amide compound containing a 1,2, 4-oxadiazole ring, and a preparation method and application thereof.
Background
Heterocyclic compounds are the most popular class of research in recent years, and five-membered heterocycles and six-membered heterocycles are mainly used as research subjects. It is known that compounds having a heterocyclic structure account for 65% or more of the total number of known compounds, and play an immeasurable role in the fields of industry, agriculture, and medicine. Due to the flexibility and variety of the types and positions of heteroatoms on the ring, heterocyclic compounds are often introduced into drug design, and nitrogen-containing heterocyclic compounds stand out from heterocyclic compounds by virtue of excellent biological activity from the condition analysis of drug development and research in recent years.
In recent years, isothiazole compounds are an emerging class of research in the agricultural field, and among agricultural chemicals, isothiazole compounds are rarely developed. To date, there are only three isothiazole agrochemicals on the market: isotianil (isotianil), benziothiazolinone (benziothiazolinone), probenazole (probenazole) and all are fungicides, another nematicide (benclothiaz) is still under development. Nevertheless, there are still a number of papers and patents relating to isothiazoles and the fact that such compounds have potential development value.
The agricultural bactericide has good bactericidal effect, but the types of germs and diseases which can be inhibited are limited, and the demand of crops is increased year by year with the rapid increase of population in recent years, but the control effect of some chemical pesticides is greatly reduced due to the generation of drug resistance, and the development of novel agricultural chemicals is very important for improving the output of food in addition to the worry of people about the problems of food safety, environmental pollution and the like.
Therefore, the development of a wider variety of novel agricultural chemicals, which have higher biological activity in agricultural pests and diseases, and effectively inhibit germs and control diseases, is urgently needed in the field.
Disclosure of Invention
The invention aims to provide a 3, 4-dichloroisothiazole amide compound containing a 1,2, 4-oxadiazole ring, which has higher biological activity in agricultural diseases and insect pests and can effectively inhibit pathogenic bacteria and prevent and control diseases.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a 3, 4-dichloroisothiazole amide compound containing a 1,2, 4-oxadiazole ring, which has a structure shown in a formula III;
in the formula III, n is 0 or 1;
in formula III, R is selected from any one of substituted or unsubstituted C-C alkyl (e.g., C), substituted or unsubstituted C-C alkoxy (e.g., C), substituted or unsubstituted C-C alkenyl (e.g., C), substituted or unsubstituted C-C heteroaryl (e.g., C, etc.), substituted or unsubstituted C-C aryl (e.g., C, etc.);
in the present invention, "C1 to C10" means that the number of carbon atoms is 1 to 10, and the meaning is given when the same expression is used.
The term "substituted or unsubstituted" as used herein means that the substituent may be substituted or unsubstituted, and for example, the substituted or unsubstituted C1-C10 alkyl group means that the C1-C10 alkyl group may have a substituent, and the number of the substituent may be one to the maximum number of the substitutable groups, or may have no substituent.
When the above-mentioned group has a substituent, the substituent includes a C to C alkyl group (e.g., C), a C to C alkoxy group (e.g., C), a C to C alkenyl group (e.g., C), a C to C aryl group (e.g., C, etc.), a C to C fluoroaryl group (e.g., C, etc.), a fluorine atom, a chlorine atom or a bromine atom, and more specifically, preferably, a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, a fluorophenyl group or a phenyl group.
The compound of the general formula III provided by the invention simultaneously contains a 1,2, 4-oxadiazole ring and a 3, 4-dichloroisothiazole group, and the heterocyclic groups with the two specific structures are matched, so that the compound has higher biological activity on agricultural diseases and insect pests, and can effectively inhibit pathogenic bacteria and prevent and control diseases.
Preferably, R is selected from any one of trifluoromethyl, methyl, methoxymethyl, hexenyl, ethyl, n-propyl, chloromethyl, dichloromethyl, trichloromethyl, 4-fluorobenzyl, styryl, 2-chloro-pyridin-3-yl, phenyl, furan-2-yl, thiophen-2-yl or 1-phenylpropyl.
Preferably, the compound shown in the formula III specifically comprises a compound shown in a formula IV, a formula V or a formula VI;
said R having the same limitations as defined in claim 1 or 2.
Preferably, in formula IV and formula V, R is selected from any one of trifluoromethyl, trichloromethyl, dichloromethyl or methoxymethyl.
The second purpose of the invention is to provide a preparation method of the 3, 4-dichloroisothiazole amide compound containing the 1,2, 4-oxadiazole ring, which comprises the following steps:
(1)3, 4-dichloroisothiazole-5-carboxylic acid reacts with cyano-substituted aniline or benzylamine to obtain an intermediate I, wherein the reaction formula is as follows:
(2) reacting the intermediate I with hydroxylamine hydrochloride to obtain an intermediate II, wherein the reaction formula is as follows:
(3) reacting the intermediate II with a compound shown as a formula A to obtain a compound shown as a formula III;
n is 0 or 1;
x is selected from chlorine atom or
The dotted line represents the access bond of the group;
r' is selected from substituted or unsubstituted C1-C10 alkyl;
the R is selected from any one of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C20 heteroaryl and substituted or unsubstituted C6-C20 aryl;
when the above groups have substituents, the substituents include C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C6-C20 aryl, C6-C20 fluoroaryl, fluorine atom, chlorine atom or bromine atom.
In the preparation method, the reaction in the step (1) is amidation reaction, the step (2) is addition reaction, and the step (3) is ring closing reaction.
Preferably, in the step (1), an acid-binding agent is added to the reaction system.
Preferably, the acid scavenger comprises any one or at least two of 4-dimethylamino pyridine, pyridine and triethylamine, preferably 4-dimethylamino pyridine.
Preferably, in step (1), the solvent for the reaction includes any one or a combination of at least two of N, N-dimethylformamide, dichloromethane, tetrahydrofuran and acetonitrile.
Preferably, in the step (1), the reaction temperature is 0 to 40 ℃, for example, 10 ℃, 15 ℃, 20 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 30 ℃, 35 ℃ and the like.
Preferably, in the step (1), the reaction time is 1-10 h, such as 2h, 3h, 4h, 5h, 6h, 6.5h, 7h, 8h, 9h and the like, and preferably 6 h.
Preferably, step (1) further comprises washing intermediate I.
Preferably, in the step (1), the intermediate I is washed with any one or a combination of at least two of hydrochloric acid, a saturated sodium carbonate solution, and a saturated brine.
Preferably, in the step (1), the concentration of the hydrochloric acid is 2-5 mol/L, such as 2.5mol/L, 3mol/L, 3.5mol/L, 4mol/L, 4.5mol/L and the like, and is preferably 3 mol/L.
Preferably, step (1) further comprises drying the intermediate I.
Preferably, in step (1), the dried desiccant comprises anhydrous sodium sulfate.
Preferably, in the step (1), the drying time is 1-3 h, such as 1.2h, 1.5h, 1.8h, 2h, 2.2h, 2.4h, 2.6h, 2.8h and the like, and preferably 2 h.
Preferably, step (1) further comprises recrystallizing intermediate I.
Preferably, in step (1), the dissolution of the recrystallization comprises dichloromethane and/or petroleum ether.
Preferably, the step (1) specifically comprises the following steps:
(a) reacting 3, 4-dichloroisothiazole-5-formic acid with oxalyl chloride to obtain 3, 4-dichloroisothiazole-5-formyl chloride, wherein the reaction formula is as follows:
(b)3, 4-dichloroisothiazole-5-formyl chloride reacts with cyano-substituted aniline or benzylamine to obtain an intermediate I, wherein the reaction formula is as follows:
and n is 0 or 1.
Preferably, in step (a), the reaction time is 25-40 min, such as 26min, 27min, 28min, 30min, 31min, 33min, 35min, 38min, etc., preferably 30 min.
Preferably, in step (a), the temperature of the reaction is-10 to 0 ℃, such as-9 ℃, -8 ℃, -7 ℃, -6 ℃, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃ and the like, preferably 0 ℃.
Preferably, in step (b), an acid-binding agent is added.
Preferably, the acid scavenger in step (b) comprises 4-dimethylaminopyridine and/or triethylamine.
Preferably, in the step (b), the reaction temperature is 23-28 ℃, such as 24 ℃, 25 ℃, 26 ℃, 27 ℃ and the like.
Preferably, in step (b), the reaction time is 5-8 h, such as 5.2h, 5.3h, 5.5h, 6h, 6.5h, 7h, 7.5h, 7.8h, etc., preferably 6 h.
Preferably, in the step (2), the reaction time is 4-6 h, such as 4.2h, 4.5h, 4.8h, 5h, 5.3h, 5.5h, 5.8h and the like, preferably 5 h.
Preferably, in step (2), the temperature of the reaction is 60 to 80 ℃, such as 61 ℃, 62 ℃, 64 ℃, 65 ℃, 68 ℃, 70 ℃, 72 ℃, 75 ℃, 78 ℃, and the like, preferably 70 ℃.
Preferably, in step (2), the solvent of the reaction comprises ethanol.
Preferably, in step (2), the intermediate I is refluxed with hydroxylamine hydrochloride in a solvent.
Preferably, step (2) further comprises extracting said intermediate II.
Preferably, in step (2), the solvent for extraction comprises ethyl acetate.
Preferably, step (2) further comprises washing the intermediate II.
Preferably, in step (2), the intermediate II is washed with a saturated saline solution.
Preferably, step (2) further comprises drying the intermediate III.
Preferably, in step (2), the drying comprises desiccant drying and/or vacuum drying.
Preferably, in step (2), the drying agent comprises anhydrous sodium sulfate.
Preferably, in step (3), the solvent for the reaction comprises toluene.
Preferably, in step (3), the intermediate II and the compound of formula a are refluxed in a solvent.
Preferably, in the step (3), the reaction time is 2-4 h, such as 2.2h, 2.5h, 2.8h, 3h, 3.5h, 3.8h and the like, and preferably 3 h.
Preferably, in the step (3), the reaction temperature is 70-90 ℃, such as 72 ℃, 75 ℃, 78 ℃, 80 ℃, 82 ℃, 85 ℃, 88 ℃ and the like, preferably 80 ℃.
Preferably, in step (3), triethylamine is added to the reaction system.
The invention also provides a bactericide, which contains the 3, 4-dichloroisothiazole amide compound containing the 1,2, 4-oxadiazole ring.
The invention also provides a bactericidal composition, which comprises an active component and an agriculturally and pharmaceutically acceptable carrier, wherein the active component is the 3, 4-dichloroisothiazole amide compound containing the 1,2, 4-oxadiazole ring.
Preferably, in the bactericidal composition, the active ingredient accounts for 1-99% of the total weight of the bactericidal composition, such as 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 98%, and the like.
The fifth purpose of the present invention is to provide an application of the 3, 4-dichloroisothiazolamide compound containing a 1,2, 4-oxadiazole ring according to one purpose, the fungicide according to the third purpose, or the fungicide composition according to the fourth purpose in pathogen inhibition or disease control.
Preferably, the pathogen comprises any one or at least two of botrytis cinerea, magnaporthe grisea, fusarium graminearum and pythium aphanidermatum.
Preferably, the disease comprises any one or at least two of soybean rust, cucumber downy mildew, cucumber powdery mildew and cucumber anthracnose.
The sixth purpose of the invention is to provide a method for preventing and controlling plant diseases, which comprises the following steps: applying an effective dose of a 1,2, 4-oxadiazole ring-containing 3, 4-dichloroisothiazolamide compound according to one of the objects, a fungicide according to the third object, or a fungicide composition according to the fourth object to a medium in need of controlling plant diseases or growth thereof.
Preferably, the effective dose is 10-1000 g per hectare, such as 12g, 20g, 50g, 100g, 150g, 200g, 250g, 300g, 350g, 400g, 450g, 500g, 550g, 600g, 650g, 700g, 750g, 800g, 850g, 900g, 950g, etc., preferably 20-500 g per hectare.
Compared with the prior art, the invention has the following beneficial effects:
the compound of the general formula III provided by the invention contains 1,2, 4-oxadiazole ring and 3, 4-dichloroisothiazole group, and the compound of the specific structure has higher biological activity in agricultural diseases and insect pests, and can effectively inhibit pathogenic bacteria and prevent and control diseases.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
In a preferred embodiment of the present invention, the compound of formula III is prepared by the following process:
(1) preparation of intermediate I:
into a dry 100mL three-necked bottle under nitrogen atmosphereAdding 3, 4-dichloroisothiazole-5-formic acid (5mmol), DMF (0.05mL) and CH in sequence2Cl2(15mL), oxalyl chloride (6mmol) was added dropwise to the flask after stirring at 0 ℃ for 10min, whereupon a large number of bubbles were formed in the reaction solution, and after 30min, the flask was allowed to cool to room temperature, whereupon the reaction was carried out until the solution became a clear, transparent, yellow-green liquid. Because the activity of acyl chloride is high, the identification is difficult generally, in order to judge whether the acyl chloride is generated, excess methanol is added into reaction liquid, and a TLC point plate (the volume ratio of petroleum ether to ethyl acetate is 1:1) judges whether the 3, 4-dichloroisothiazole-5-formic acid is completely reacted. After the reaction, the resulting liquid was transferred to a dry dropping funnel and added dropwise at a low temperature to a solution containing cyano-substituted aniline or benzylamine (5mmol), DMAP (9mmol), CH2Cl2In another three-necked flask (30mL), the reaction was carried out at room temperature for about 6 hours, and TLC detection was carried out (the volume ratio of petroleum ether to ethyl acetate was 1: 1). After the reaction, 30mL of water was added, the organic phase was separated, and 60mL of hydrochloric acid (3mol/L) and 60mL of saturated Na were used in this order2CO3The solution was washed with 60mL of a saturated saline solution and anhydrous Na2SO4Drying for 2h, performing suction filtration, removing the solvent to obtain a crude product, obtaining an intermediate I by adopting a dichloromethane and petroleum ether recrystallization method, and drying the intermediate I in vacuum for later use.
(2) Preparation of intermediate II:
adding the intermediate I (23mmol), hydroxylamine hydrochloride (69mmol), triethylamine (92mmol) and 70mL of ethanol into a 100mL three-necked flask at room temperature, refluxing at 70 ℃ for 5h, then observing that the solution becomes clear and yellow, detecting by TLC (the volume ratio of petroleum ether to ethyl acetate is 2:1), cooling the reaction solution after the raw materials completely react, spinning off the ethanol, extracting the residue with 60mL of ethyl acetate, washing with 60mL of saturated saline solution twice, collecting an organic phase, and adding anhydrous Na2SO4Drying, spin-drying to obtain intermediate II, and vacuum drying.
(2) Preparation of 3, 4-dichloroisothiazole amide compound III containing 1,2, 4-oxadiazole ring:
anhydrous intermediate II (2mmol) and 15mL of toluene were added to a 50mL three-necked flask and the R-substituted acid chloride or anhydride (R-substituted carboxylic acid chloride or anhydride) ((R-substituted carboxylic acid anhydride)) was added
2mmol) in 5mL of toluene, slowly adding the reaction solution in ice bath, stirring for 30min, refluxing at 80 ℃ for 3h, and detecting by TLC (the volume ratio of petroleum ether to ethyl acetate is 2: 1). If the reaction is slow, adding a small amount of triethylamine, spinning to dry the toluene after the raw materials completely react, dissolving the residue with a small amount of tetrahydrofuran, and passing through a chromatographic column (the volume ratio of petroleum ether to ethyl acetate is 4: 1)]Purifying by a method to obtain the 3, 4-dichloroisothiazole amide compound III containing the 1,2, 4-oxadiazole ring.
Illustratively, the following examples set forth synthetic methods for representative specific compounds:
example 1
This example provides a method for the synthesis of compound III-1, as follows:
(1) synthesis of intermediate I-1: to a dry 100mL three-necked flask, 3, 4-dichloroisothiazole-5-carboxylic acid (5mmol), DMF (0.05mL), CH were added in that order under nitrogen2Cl2(15mL), oxalyl chloride (6mmol) was added dropwise to the flask after stirring at 0 ℃ for 10min, whereupon a large number of bubbles were formed in the reaction solution, and after 30min, the flask was allowed to cool to room temperature, whereupon the reaction was carried out until the solution became a clear, transparent, yellow-green liquid. Since the activity of acyl chloride is high, it is difficult to identify the acyl chloride, and in order to determine whether acyl chloride is generated, excess methanol is added into the reaction solution, and TLC spot plate (V)Petroleum ether：VEthyl acetate1:1) was judged whether 3, 4-dichloroisothiazole-5-carboxylic acid reacted completely. After the reaction, the resulting liquid was transferred to a dry dropping funnel and added dropwise at a low temperature to the reaction mixture containing 3-cyanobenzylamine (5mmol), DMAP (9mmol), CH2Cl2(30mL) in another three-necked flask, the reaction was carried out at room temperature for about 6 hours, and TLC detection (V)Petroleum ether：VEthyl acetate1:1), then 30mL of water was added to the reaction flask, the organic phase was separated, and 30mL of hydrochloric acid (3mol/L) and 30mL of saturated Na were used in this order2CO3The solution was washed with 30mL of a saturated saline solution and anhydrous Na2SO4Drying for 2h, performing suction filtration, removing the solvent to obtain a crude product, obtaining an intermediate I-1 by adopting a dichloromethane and petroleum ether recrystallization method, and drying the intermediate I-1 in vacuum for later use.
(2) Synthesis of intermediate II-1: adding into a 100mL three-necked bottle at room temperatureAdding intermediate I-1(23mmol), hydroxylamine hydrochloride (69mmol), triethylamine (92mmol) and 70mL ethanol, refluxing at 70 deg.C for 5h to observe that the solution becomes clear and yellow, and detecting by TLC (V)Petroleum ether：VEthyl acetate2:1), cooling the reaction solution after the raw materials completely react, removing ethanol by rotary evaporation, extracting the residue with 60mL of ethyl acetate, washing with 60mL of saturated saline solution twice, collecting the organic phase, and collecting anhydrous Na2SO4Drying, rotary steaming to obtain intermediate II-1, and vacuum drying.
(3) Synthesis of Compound III-1: adding intermediate II-1(2mmol) and 15mL of toluene into a 50mL three-necked flask under anhydrous condition, dissolving trifluoroacetic anhydride (2mmol) in 5mL of toluene, slowly adding the reaction solution under ice bath, stirring for 30min, refluxing at 80 ℃ for 3h, and detecting by TLC (V)Petroleum ether：VEthyl acetate2: 1). If the reaction is slow, adding a small amount of triethylamine, spinning off the solvent after the raw materials react completely, dissolving the residue with a small amount of tetrahydrofuran, and passing through a chromatographic column [ V ]Petroleum ether:VEthyl acetate＝4:1]Purifying to obtain compound III-1
Example 2
This example provides a method for the synthesis of compound III-17, as follows:
(1) synthesis of intermediate I-2: to a dry 100mL three-necked flask, 3, 4-dichloroisothiazole-5-carboxylic acid (5mmol), DMF (0.05mL), CH were added in that order under nitrogen2Cl2(15mL), oxalyl chloride (6mmol) was added dropwise to the flask after stirring at 0 ℃ for 40min, whereupon a large number of bubbles were formed in the reaction solution, and after 30min, the flask was allowed to cool to room temperature, whereupon the reaction was carried out until the solution became a clear, transparent, yellow-green liquid. Since the activity of acyl chloride is high, it is difficult to identify the acyl chloride, and in order to determine whether acyl chloride is generated, excess methanol is added into the reaction solution, and TLC spot plate (V)Petroleum ether：VEthyl acetate1:1) was judged whether 3, 4-dichloroisothiazole-5-carboxylic acid reacted completely. After the reaction, the resulting liquid was transferred to a dry dropping funnel and added dropwise at low temperature to the flask containing 3-cyanoaniline (5mmol), DMAP (9mmol), CH2Cl2(30mL) in another three-necked flask, the reaction was carried out at 23 ℃ for about 8 hours, and TLC detection (V)Petroleum ether：VEthyl acetate1:1), then 30mL of water was added to the reaction flask, the organic phase was separated and washed successively with 30mL of hydrochloric acid (2mol/L) and 30mL of saturated Na2CO3The solution was washed with 30mL of a saturated saline solution and anhydrous Na2SO4Drying for 1h, performing suction filtration, removing the solvent to obtain a crude product, obtaining an intermediate I-2 by adopting a dichloromethane and petroleum ether recrystallization method, and drying the intermediate I-2 in vacuum for later use.
(2) Synthesis of intermediate II-2: at room temperature, the intermediate I-2(23mmol), hydroxylamine hydrochloride (69mmol), triethylamine (92mmol) and 70mL ethanol were added to a 100mL three-necked flask, and after refluxing at 60 ℃ for 6h, the solution became clear and yellow as observed by TLC (V)Petroleum ether：VEthyl acetate2:1), cooling the reaction solution after the raw materials completely react, removing ethanol by rotary evaporation, extracting the residue with 60mL of ethyl acetate, washing with 60mL of saturated saline solution twice, collecting the organic phase, and collecting anhydrous Na2SO4Drying, rotary steaming to obtain intermediate II-2, and vacuum drying.
(3) Synthesis of Compound III-17: adding intermediate II-2(2mmol) and 15mL of toluene into a 50mL three-necked flask under anhydrous condition, dissolving trifluoroacetic anhydride (2mmol) in 5mL of toluene, slowly adding the reaction solution under ice bath, stirring for 30min, refluxing at 90 ℃ for 2h, and detecting by TLC (V)Petroleum ether：VEthyl acetate2: 1). If the reaction is slow, adding a small amount of triethylamine, spinning off the solvent after the raw materials react completely, dissolving the residue with a small amount of tetrahydrofuran, and passing through a chromatographic column [ V ]Petroleum ether:VEthyl acetate＝4:1]Purifying to obtain compound III-17
Example 3
This example provides a method for the synthesis of compound III-20, as follows:
(1) synthesis of intermediate I-3: to a dry 100mL three-necked flask, 3, 4-dichloroisothiazole-5-carboxylic acid (5mmol), DMF (0.05mL), CH were added in that order under nitrogen2Cl2(15mL), stirring at-10 ℃ for 10min, then adding oxalyl chloride (6mmol) dropwise into the reaction flask, wherein a large amount of bubbles are generated in the reaction solution, moving to room temperature after 25min, and reacting until the solution becomes clear and transparent yellow-green liquid. Since the activity of acyl chloride is high, it is difficult to identify the acyl chloride, and in order to determine whether acyl chloride is generated, excess methanol is added into the reaction solution, and TLC spot plate (V)Petroleum ether：VEthyl acetate1:1) was judged whether 3, 4-dichloroisothiazole-5-carboxylic acid reacted completely. After the reaction, the resulting liquid was transferred to a dry dropping funnel and added dropwise at low temperature to a solution containing 4-cyanoaniline (5mmol), DMAP (9mmol), CH2Cl2(30mL) in another three-necked flask, the reaction was carried out at 28 ℃ for about 5 hours, and TLC detection (V)Petroleum ether：VEthyl acetate1:1), then 30mL of water was added to the reaction flask, the organic phase was separated and washed successively with 30mL of hydrochloric acid (4mol/L) and 30mL of saturated Na2CO3The solution was washed with 30mL of a saturated saline solution and anhydrous Na2SO4Drying for 2h, performing suction filtration, removing the solvent to obtain a crude product, obtaining an intermediate I-3 by adopting a dichloromethane and petroleum ether recrystallization method, and drying the intermediate I-3 in vacuum for later use.
(2) Synthesis of intermediate II-3: at room temperature, the intermediate I-3(23mmol), hydroxylamine hydrochloride (69mmol), triethylamine (92mmol) and 70mL ethanol were added to a 100mL three-necked flask, and after refluxing at 80 ℃ for 4h, the solution became clear and yellow as observed by TLC (V)Petroleum ether：VEthyl acetate2:1), cooling the reaction solution after the raw materials completely react, removing ethanol by rotary evaporation, extracting the residue with 60mL of ethyl acetate, washing with 60mL of saturated saline solution twice, collecting the organic phase, and collecting anhydrous Na2SO4Drying, rotary steaming to obtain intermediate II-3, and vacuum drying.
(3) Synthesis of Compound III-20: adding the intermediate II-3(2mmol) and 15mL of methylbenzene into a 50mL three-necked bottle under anhydrous condition, dissolving trifluoroacetic anhydride (2mmol) in 5mL of methylbenzene, slowly adding the reaction solution under ice bath, stirring for 30min, refluxing at 85 ℃ for 4h, and detecting by TLC (V)Petroleum ether：VEthyl acetate2: 1). If the reaction is slow, adding a small amount of triethylamine, spinning off the solvent after the raw materials react completely, and using a small amount of tetrahydrofuran to obtain residuesDissolving pyran, passing through chromatographic column [ V ]Petroleum ether:VEthyl acetate＝4:1]Purifying to obtain compound III-20
The examples of the invention partially synthesize 22 specific compounds (III-1 to III-22), and the synthesis method of the compounds is the same as that of the compounds III-1, III-17 and III-20 and can be realized by replacing raw materials. Thus, not listed, Table 1 shows the structural and physicochemical data for intermediates II-1 to II-2 and compounds III-1 to III-22, and Table 2 shows the nuclear magnetic hydrogen spectra, mass spectra and elemental analysis data for intermediates II-1 to II-2 and compounds III-1 to III-22. Wherein nuclear magnetic hydrogen spectrum data is measured by a Bruker300-MHz type nuclear magnetic resonance instrument, mass spectrum data is measured by Agilent gas chromatography (7890B) -triple quadrupole tandem mass spectrometer, and elemental analysis data is measured by a Flash EA 1112 type elemental analyzer.
TABLE 1
TABLE 2
Comparative example 1
This comparative example provides a compound containing only 3, 4-dichloroisothiazole (compound D1) prepared as follows:
to a dry 100mL three-necked flask, 3, 4-dichloroisothiazole-5-carboxylic acid (5mmol), DMF (0.05mL), CH were added in that order under nitrogen2Cl2(15mL), after stirring at 0 ℃ for 10min, oxalyl chloride (6mmol) was added dropwise to the flask, and after 30min, the flask was allowed to warm to room temperature, and the reaction was allowed to proceed until the solution became a clear, transparent, yellow-green liquid. The liquid was transferred to a dry dropping funnel and added dropwise at low temperature to a solution containing 2-cyanoaniline (5mmol), DMAP (9mmol), CH2Cl2(30mL) in another three-necked flask, the reaction was carried out at room temperature for about 6 hours, and TLC detection (V)Petroleum ether：VEthyl acetate1:1), then 30mL of water was added to the reaction flask, the organic phase was separated, and 30mL of hydrochloric acid (3mol/L) and 30mL of saturated Na were used in this order2CO3The solution was washed with 30mL of a saturated saline solution and anhydrous Na2SO4Drying for 2h, filtering, removing the solvent to obtain a crude product, and recrystallizing by dichloromethane and petroleum ether to obtain a compound D1. The melting range is 196.1-196.8 ℃,1H NMR(600MHz,DMSO-d6)δ11.04(s，1H)，7.49-7.93(m，4H)。
test example 1 in vitro bactericidal Activity assay
The in vitro bactericidal activity assay was performed on intermediates II-1 to II-3 and compounds III-1 to III-22, using the following specific test methods:
under the in vitro condition, selecting Botrytis cinerea (Botrytis cinerea), Pyricularia oryzae (Pyricularia grisea), Pythium aphanidermatum (Pythium aphanidermatum) and Fusarium graminearum (Fusarium graminearum) as test strains for active screening, and respectively preparing test agents into mother liquor of 5000 mu g/mL by using acetone for standby. Under a sterile super clean bench, 30mL of Potato Dextrose Agar (PDA) culture medium is measured, 300 mu L of mother liquor is added and uniformly shaken, the mixture is evenly poured into three 9cm culture dishes, after the culture medium is solidified, fungus cakes are inoculated, 3 groups of treatments are repeated, acetone is used as a blank control, and the culture is carried out at 25 ℃. When the blank control hyphae were grown to 2/3 on the petri dish, the diameter was measured by the cross method, and the inhibition rate of the target compound on the hyphae growth at a concentration of 50. mu.g/mL was calculated, and the test results are shown in Table 3.
TABLE 3
In Table 3, "-" represents no measurement.
As is clear from Table 3, the measurement results by the hyphal growth rate method show that: under 50 mu g/mL, the compound provided by the invention has an inhibiting effect on the four pathogenic bacteria. The inhibition rate of most compounds on botrytis cinerea is over 50 percent, wherein the inhibition rate of the compounds III-3, III-10 and III-12 is over 70 percent. For Pyricularia oryzae, the inhibition rate of most compounds was 30% or more, and the most effective inhibition was compound III-9, which had an inhibition rate of 58.53%. For pythium aphanidermatum, the inhibition rate of the compound provided by the invention is between 5% and 65%, wherein the inhibition rate of the compound III-7 is 63.28%. For fusarium graminearum, the inhibitory activity of the compounds III-2, III-3, III-7 and III-20 reaches more than 40 percent.
Therefore, the compound provided by the invention can effectively inhibit pathogenic bacteria.
Test example 2 in vivo bactericidal Activity test
Aiming at the intermediates II-1 to II-3 and the compounds III-1 to III-22, the control effects of the compounds provided by the invention on soybean rust (Phakopsora pachyrhizi), cucumber downy mildew (Pseudoperonospora cubensis), cucumber powdery mildew (Sphaerotheca Fuliginea) and cucumber anthracnose (Colletotrichum orbiculare) are determined by using a living pot culture method, and the specific steps are as follows:
a sample of a compound to be tested is dissolved by a small amount of solvent (the type of the solvent is selected according to the dissolving capacity of the solvent on the sample, and the volume ratio of the solvent amount to the liquid spraying amount is equal to or less than 0.05), and diluted by water containing 0.1% of Tween 80 to prepare a liquid to be tested with a required concentration. Foliar spray treatments were performed with test compounds at the designed concentrations. And additionally arranging a blank control sprayed with clear water, repeating for 3 times, and performing disease inoculation 24 hours after treatment. After inoculation, the plants are placed in a moisture-preserving room for moisture-preserving culture (temperature: 25 ℃ in the day, 20 ℃ in the night, relative humidity: 95-99%). After the test material is cultured for 24h, the test material is moved to a greenhouse for culture, and pathogenic bacteria which do not need to be subjected to moisture-keeping culture are inoculated to crops and then directly placed in the greenhouse for culture. The compound disease control effect evaluation is carried out after the control is sufficiently ill (usually, one week). The results were examined with reference to the American society for Plant Diseases, A Manual of Association, expressed as 100-0, with "100" representing no disease and "0" representing the most severe degree of disease.
The test results are shown in table 4.
TABLE 4
In Table 4, "-" indicates no measurement.
In table 4, benzovindiflupyr, fluopicolide, ethirimol and prochloraz are all the existing fungicides and are commercially available.
As can be seen from Table 4, at a concentration of 10mg/L, the control effect of the compounds III-1, III-3 and III-22 provided by the invention on soybean rust exceeds 30%. At the concentration of 100mg/L, the control effect of the compound III-2 on cucumber downy mildew is 75%, the control effect of the compounds III-11, III-18, III-20 and III-22 on cucumber powdery mildew is more than 40%, wherein the control effect of the compound III-18 is 60%, and the control effect of the compounds III-4, III-8, III-14, III-15, III-16 and III-18 on cucumber anthracnose is more than 80%, wherein the control effect of the compound III-18 is the most excellent, the control effect is 95%, and is similar to that of prochloraz.
Test example 3 insecticidal Activity test
The test example determines the insecticidal activity of partial intermediates and compounds, and a leaf virus trapping method is adopted to determine the lethality of the compounds provided by the invention to diamondback moths, and the specific steps refer to the agricultural industry standard of the people's republic of China (NY/T1154.14-2008) -pesticide part 14 of the indoor bioassay test criteria of pesticides: leaf soaking method.
The results are shown in Table 5.
TABLE 5
The results in table 5 show: when the test concentration is 10mg/L, the other compounds except the intermediate II-3 have toxic and killing effects on diamond back moths after being applied for 3 days.
As can be seen from the data in tables 3 to 5, the compound D1 has mediocre effects of inhibiting germs and controlling diseases, and does not exhibit outstanding effects; the 1,2, 4-oxadiazole ring is introduced, so that the compound can show excellent inhibition and prevention effects on certain germs and diseases.
The present invention is illustrated in detail by the examples described above, but the present invention is not limited to the details described above, i.e., it is not intended that the present invention be implemented by relying on the details described above. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A 3, 4-dichloroisothiazolamide compound containing a 1,2, 4-oxadiazole ring, which is characterized by having a structure shown in formula III;
in the formula III, n is 0 or 1;
in the formula III, R is selected from any one of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C20 heteroaryl and substituted or unsubstituted C6-C20 aryl;
when the above groups have substituents, the substituents include C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C6-C20 aryl, C6-C20 fluoroaryl, fluorine atom, chlorine atom or bromine atom.
2. The 1,2, 4-oxadiazole ring-containing 3, 4-dichloroisothiazolamide-based compound of claim 1, wherein R is selected from any one of trifluoromethyl, methyl, methoxymethyl, hexenyl, ethyl, n-propyl, chloromethyl, dichloromethyl, trichloromethyl, 4-fluorobenzyl, styryl, 2-chloro-pyridin-3-yl, phenyl, furan-2-yl, thiophen-2-yl, and 1-phenylpropyl.
3. The 1,2, 4-oxadiazole ring-containing 3, 4-dichloroisothiazolamide-based compound according to claim 1 or 2, wherein the compound represented by formula III specifically includes a compound represented by formula IV, formula V or formula VI;
said R having the same limitations as defined in claim 1 or 2.
4. The 1,2, 4-oxadiazole ring-containing 3, 4-dichloroisothiazolamide-based compound of claim 3, wherein in formula IV and formula V, R is selected from any one of trifluoromethyl, trichloromethyl, dichloromethyl and methoxymethyl.
5. A preparation method of the 3, 4-dichloroisothiazolamide compound containing 1,2, 4-oxadiazole ring according to any one of claims 1 to 4, characterized by comprising the following steps:
(1)3, 4-dichloroisothiazole-5-carboxylic acid reacts with cyano-substituted aniline or benzylamine to obtain an intermediate I, wherein the reaction formula is as follows:
(2) reacting the intermediate I with hydroxylamine hydrochloride to obtain an intermediate II, wherein the reaction formula is as follows:
(3) the intermediate II reacts with a compound shown as a formula A to obtain the 3, 4-dichloroisothiazole amide compound containing the 1,2, 4-oxadiazole ring;
n is 0 or 1;
x is selected from chlorine atom or
The dotted line represents the access bond of the group;
r' is selected from substituted or unsubstituted C1-C10 alkyl;
the R is selected from any one of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C20 heteroaryl and substituted or unsubstituted C6-C20 aryl;
when the above groups have substituents, the substituents include C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C6-C20 aryl, C6-C20 fluoroaryl, fluorine atom, chlorine atom or bromine atom.
6. The preparation method according to claim 5, wherein in the step (1), an acid-binding agent is added to the reaction system;
preferably, the acid-binding agent comprises any one or at least two of 4-dimethylamino pyridine, pyridine and triethylamine, preferably 4-dimethylamino pyridine;
preferably, in the step (1), the solvent for the reaction includes any one or a combination of at least two of N, N-dimethylformamide, dichloromethane, tetrahydrofuran and acetonitrile;
preferably, in the step (1), the reaction temperature is 0-40 ℃;
preferably, in the step (1), the reaction time is 1-10 h, preferably 6 h;
preferably, step (1) further comprises washing intermediate I;
preferably, in the step (1), the intermediate I is washed by using any one or at least two of hydrochloric acid, saturated sodium carbonate solution and saturated brine;
preferably, in the step (1), the concentration of the hydrochloric acid is 2-5 mol/L, and preferably 3 mol/L;
preferably, step (1) further comprises drying intermediate I;
preferably, in step (1), the dried desiccant comprises anhydrous sodium sulfate;
preferably, in the step (1), the drying time is 1-3 h, preferably 2 h;
preferably, step (1) further comprises recrystallizing intermediate I;
preferably, in step (1), the dissolution of the recrystallization comprises dichloromethane and/or petroleum ether;
preferably, the step (1) specifically comprises the following steps:
(a) reacting 3, 4-dichloroisothiazole-5-formic acid with oxalyl chloride to obtain 3, 4-dichloroisothiazole-5-formyl chloride, wherein the reaction formula is as follows:
(b)3, 4-dichloroisothiazole-5-formyl chloride reacts with cyano-substituted aniline or benzylamine to obtain an intermediate I, wherein the reaction formula is as follows:
n is 0 or 1;
preferably, in the step (a), the reaction time is 25-40 min, preferably 30 min;
preferably, in the step (a), the temperature of the reaction is-10-0 ℃, and preferably 0 ℃;
preferably, in step (b), an acid-binding agent is added;
preferably, in step (b), the acid scavenger comprises 4-dimethylaminopyridine and/or triethylamine;
preferably, in the step (b), the temperature of the reaction is 23-28 ℃;
preferably, in the step (b), the reaction time is 5-8 h, preferably 6 h;
preferably, in the step (2), the reaction time is 4-6 h, preferably 5 h;
preferably, in the step (2), the reaction temperature is 60-80 ℃, and preferably 70 ℃;
preferably, in step (2), the solvent of the reaction comprises ethanol;
preferably, in the step (2), the intermediate I and hydroxylamine hydrochloride are refluxed in a solvent;
preferably, step (2) further comprises extracting the intermediate II;
preferably, in step (2), the extracted solvent comprises ethyl acetate;
preferably, step (2) further comprises washing the intermediate II;
preferably, in the step (2), the intermediate II is washed by using saturated saline;
preferably, step (2) further comprises drying the intermediate III;
preferably, in step (2), the drying comprises desiccant drying and/or vacuum drying;
preferably, in step (2), the drying agent comprises anhydrous sodium sulfate;
preferably, in step (3), the solvent of the reaction comprises toluene;
preferably, in step (3), the intermediate II and the compound of formula a are refluxed in a solvent;
preferably, in the step (3), the reaction time is 2-4 h, preferably 3 h;
preferably, in the step (3), the reaction temperature is 70-90 ℃, preferably 80 ℃;
preferably, in step (3), triethylamine is added to the reaction system.
7. A bactericide, characterized in that the bactericide contains the 1,2, 4-oxadiazole ring-containing 3, 4-dichloroisothiazolamide-based compound according to any one of claims 1 to 4.
8. A bactericidal composition, which is characterized by comprising an active component and an agriculturally pharmaceutically acceptable carrier, wherein the active component is the 3, 4-dichloroisothiazolamide compound containing the 1,2, 4-oxadiazole ring according to any one of claims 1 to 4;
preferably, in the bactericide composition, the active ingredient accounts for 1-99% of the total weight of the bactericide composition.
9. Use of the 1,2, 4-oxadiazole ring-containing 3, 4-dichloroisothiazolamide compound according to any one of claims 1 to 4, the fungicide according to claim 7 or the fungicidal composition according to claim 8 for pathogen inhibition or disease control;
preferably, the germs comprise any one or at least two of botrytis cinerea, rice blast, fusarium graminearum and pythium aphanidermatum;
preferably, the disease comprises any one or at least two of soybean rust, cucumber downy mildew, cucumber powdery mildew and cucumber anthracnose.
10. A method for controlling plant diseases, comprising: applying an effective amount of the 1,2, 4-oxadiazole ring-containing 3, 4-dichloroisothiazolamide compound according to any one of claims 1 to 4, the fungicide according to claim 7 or the fungicidal composition according to claim 8 to a medium in need of controlling plant diseases or growth thereof;
preferably, the effective dose is 10-1000 g per hectare, preferably 20-500 g per hectare.
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