JP2845553B2 - Nitrothiophene compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial application field) The present invention provides a novel nitrothiophene compound useful as a fungicide and a fungicide.

(Prior Art and Problems to be Solved by the Invention) Conventionally, various synthesis examples of nitrothiophene compounds in which another organic group is bonded to a nitrothiophene ring via an ether group have been reported. For example, the compound represented by the following general formula (A) is described in Annalen de Chimmy (Ann. Chim. (Rome), pp. 54,281, 1964 ).

(However, R represents a group selected from hydrogen, methyl group, chlorine and bromine.) Also, Journal of American Chemical Society (J. Am. Chem. Soc., 74, 2965, p. 1952 ) A compound represented by the following general formula (B) is described.

(However, R represents an alkyl group or a phenyl group.) However, none of these documents describes the fungicidal / fungicidal activity of the nitrothiophene compound.
Further, as a result of the confirmation by the present inventors, almost no bactericidal or fungicidal activity was recognized for these compounds.

[Means for solving the problem]

The present inventors have studied the synthesis of new nitrothiophene compounds and the fungicidal and fungicidal activities.

As a result, the nitrothiophene compound represented by the general formula (1) shows a very high bactericidal / fungicidal effect even when compared with a commercially available bactericide / fungicide described later, and the nitrothiophene compound represented by the general formula (1) shown in the present invention. The present inventors have confirmed that a nitrothiophene compound can be a promising fungicide and fungicide, and have completed the present invention.

That is, the present invention relates to general formula (1): (However, X ₁ , X ₂ , X ₃ , X ₄ and X ₅ represent a hydrogen atom, a halogen atom, a formyl group, a nitro group, a cyano group, a hydroxyl group,
Hetero or similar groups selected from an alkoxy group, an alkylthio group, a monoalkylamino group, a dialkylamino group, an alkoxycarbonyl group, a substituted or unsubstituted alkyl group, an alkenyl group and an alkynyl group, and a substituted or unsubstituted phenyl group Is shown. A nitrothiophene compound represented by the formula:

In the present invention, in the general formula (1), X ₁ , X ₂ , X ₃ ,
Specifically, as the halogen atom represented by X ₄ and X ₅ ,
Each of the atoms of chlorine, bromine, fluorine and iodine has an alkyl group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, an alkoxysulfonyl group, a monoalkylamino group and an alkyl residue in the alkylamino group having 1 carbon atom
Preferred are those having up to 4 linear or branched chains. As the alkyl group and the alkyl residue, specifically, methyl group, ethyl group, n-propyl group, iso-propyl group,
Examples include an n-butyl group, an iso-butyl group, a tert-butyl group, and the like.

When a dialkylamino group is specifically exemplified, a dimethylamino group, a diethylamino group, a di-n-propylamino group, a di-iso-propylamino group, a di-n-butylamino group, a methyl-ethylamino group, Methyl-n-propylamino group, methyl-iso-propylamino group, methyl-n-butylamino group, ethyl-n-propylamino group, ethyl-iso-propylamino group, ethyl-n-
Examples thereof include a butylamino group and an n-propyl-n-butylamino group.

In the present invention, in the general formula (1), X ₁ , X ₂ , X ₃ ,
As the substituent of the substituted alkyl group represented by X ₄ and X _{5, those in} which all or part of the hydrogen in the alkyl group is substituted with a halogen atom, an alkoxy group, an alkylthio group, a cyano group, or the like are preferable. Specific examples of such a substituted alkyl group include a chloromethyl group, a bromomethyl group, a fluoromethyl group, an iodomethyl group, a dichloromethyl group, a chlorodifluoromethyl group, a difluoromethyl group, a trichloromethyl group, a trifluoromethyl group, and a methoxymethyl group. ,
Ethoxymethyl, methylthiomethyl, cyanomethyl, chloroethyl, bromoethyl, fluoroethyl, dichloroethyl, dibromoethyl, difluoroethyl, trichloroethyl, trifluoroethyl, perfluoroethyl, perfluoropropyl Group,
Examples include a methoxyethyl group, an ethoxyethyl group, a methoxypropyl group, a methylthioethyl group, an ethylthioethyl group, a cyanoethyl group, a cyanopropyl group, and the like.

In the present invention, in the general formula (1), X ₁ , X ₂ , X ₃ ,
As the alkenyl group represented by X ₄ and X ₅ , a linear or branched one having 1 to 4 carbon atoms is suitably used. Specific examples of the alkenyl group include a vinyl group, an allyl group, a propenyl group, a 2-butenyl group, and a 3-butenyl group.

In the present invention, X ₁ , X ₂ , X ₃ ,
As the alkynyl group represented by X ₄ and X ₅ , a linear or branched alkynyl group having 1 to 4 carbon atoms is suitably used. Specific examples of the alkynyl group include an ethynyl group, 2
-Propynyl group, 1-butynyl group, 2-butynyl group, 3
-Butynyl group and the like.

Further, as the substituted phenyl group, one or more hydrogen atoms on the aromatic ring are different or the same halogen atom,
Those substituted with an alkyl group, an alkoxy group, an alkylthio group, a cyano group, an alkoxycarbonyl group and the like are preferable. Specific examples of such a substituted phenyl group include chlorophenyl, bromophenyl, fluorophenyl, iodophenyl, dichlorophenyl, trichlorophenyl, chloro-methylphenyl, bromo-fluorophenyl, and chloro- Ethylphenyl group,
Chloro-cyanophenyl group, chloro-methoxycarbonylphenyl group, methyl-ethylphenyl group, trimethylphenyl group, cyanotolyl group, methylthiotolyl group, trimethoxyphenyl group, tetrachlorophenyl group, chloro-dimethylphenyl group, methoxyphenyl group, ethoxy group Phenyl group, isopropoxyphenyl group, ethylthiophenyl group, dichloro-cyanophenyl group, dichloro-
An ethoxycarbonylphenyl group and the like can be mentioned.

The structure of the nitrothiophene compound of the present invention represented by the general formula (1) can be confirmed by the following means.

(B) By measuring the infrared absorption spectrum (IR), an absorption based on an ether bond was observed around 1250 to 1200 cm,
~ 1510cm and absorption around 1350 ~ 1320cm based on nitro group,
A special absorption based on an aromatic ring can be observed around 1600 to 1500 cm. As a representative example, the infrared absorption spectrum of 33-pyridyloxy) -2-nitrothiophene is shown in FIG.

(B) Measure mass spectrum (MS)
Peak (generally, ion molecular weight m is expressed as ion charge number e)
Is calculated by dividing by m / e divided by m / e)
The molecular weight of the compound subjected to the measurement and the molecular weight
You can know the bonding style of each atomic group within. Immediately
The general formula of the sample used for measurementIn general, the molecular ion peak (hereinafter referred to as M Abbreviated
Depends on the number of halogen atoms contained in the molecule.
Is observed at an intensity according to the isotope abundance ratio.
The molecular weight of the compound subjected to the above can be determined. Ma
Further, for the compound represented by the general formula,Characteristic peaks corresponding to the
You can know the matching style.

By measuring the (c) ¹ H- nuclear magnetic resonance spectra ⁽¹ H-NMR), it is possible to know the binding mode of the hydrogen atoms present in the compounds of the present invention represented by the general formula.
Regardless of the type of X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ in the general formula (1), protons such as thiophene ring and pyridine ring are 6.
It generally appears as a multiline at around 0 to 8.5 ppm.

FIG. 2 shows a ¹ H-NMR diagram of 3 (3-pyridyloxy) -2-nitrothiophene as a typical example of ¹ H-NMR (δ ppm: tetramethylsilane, deuterated chloroform solvent) of the compound. The analysis results are as follows.

That is, a double line corresponding to one proton is recognized at 6.59.ppm, which can be attributed to the proton He. 7.11
Multiplet was observed corresponding to three cycles of proton ～7.51Ppm, it can be assigned protons H _c, H _d, to be due to H _b. 8.
Multiplet corresponding to two pieces of protons observed 21～8.91Ppm, it can be assigned to be due to protons H _a, H _f.

(D) By elemental analysis, the weight percentages of carbon, hydrogen, nitrogen, and sulfur (if halogen is contained) are determined,
Further, by subtracting the perceived sum of the weight percentages of each element from 100, the weight percentage of oxygen can be calculated, and thus the composition formula of the compound can be determined.

The nitrothiophene compound of the present invention is generally a yellow or tan solid at normal temperature and pressure.

The derivatives of the present invention are benzene, ether, alcohol,
It is well soluble in organic solvents such as acetone, N, N-dimethylformamide and dimethylsulfoxide, but is insoluble in water.

The method for producing the nitrothiophene compound of the present invention represented by the general formula (1) is not particularly limited, and may be produced by any production method.

Examples of typical production methods include: (a) general formula (2), (Where X ₆ represents a halogen atom, and X ₁ , X ₂ and X ₃ are as shown in the general formula (1).) A halogenopyridine compound of the general formula (3) (Where X ₄ and X ₅ are as shown in the general formula (1)), a method of reacting the compound with a hydroxythiophene compound in the presence of a hydrogen halide scavenger, in the presence or absence of a solvent, or Is (b) general formula (4), (Where X ₁ , X ₂ , and X ₃ are as shown in the general formula (1).) (Where X ₆ represents a halogen atom, and X ₄ and X ₅ are as shown in the general formula (1)), and the presence or absence of a solvent in the presence of a hydrogen halide scavenger. It can be produced by a method of reacting in the presence.

In the above method (a), the charged molar ratio of the halogenopyridine compound represented by the general formula (2) and the hydroxythiophene compound represented by the general formula (3) may be appropriately determined as needed, but may be usually determined. It is common to use a slight excess of the molar or hydroxythiophene compound.

In the above method (b), the charged molar ratio of the halogenothiophene compound represented by the general formula (5) and the hydroxypyridine compound represented by the general formula (4) may be appropriately determined as needed, but may be usually determined. It is common to use a slight excess of the molar or hydroxypyridine compound.

The solvent used in the above methods (a) and (b) is generally benzene, toluene, xylene,
Methylene chloride, chloroform, N, N-dimethylformamide and the like are preferably used. In addition, in order to capture hydrogen halide by-produced in the reactions in the above methods (a) and (b), it is usually preferable to coexist a hydrogen halide capturing agent in the reaction system. The hydrogen halide scavenger is not particularly limited, and known ones can be used. However, trialkylamines such as triethylamine, trimethylamine, and tripropylamine, pyridine, and sodium alcoholate are generally preferably used. ,
Examples include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like.

Further, in the reaction of each method, the hydroxythiophene compound represented by the general formula (3) and the hydroxypyridine compound represented by the general formula (4) may be used by previously reacting with an alkali metal to prepare an alcoholate.

Further, in the reaction of each method, the reaction temperature is from room temperature to 200
Although the range of ° C can be generally adopted, it is preferred to carry out in the range of 50 to 150 ° C. The reaction time is 0.5-40
The treatment is carried out within a time range, but is preferably carried out for 8 to 15 hours.

The method for isolating and purifying the nitrothiophene compound as the target product from the reaction system is not particularly limited, and a known method can be employed. The reaction solution is added to ice water, and the resulting solid is separated by filtration.The solid is recrystallized or purified by column chromatography.If the solvent is not mixed with water, the reaction solution is added to water. After extraction and removal of the solvent, a method of purifying the residue by recrystallization or column chromatography is suitably used.

(Effect)

The nitrothiophene compound represented by the general formula (1) of the present invention has strong antibacterial activity against phytopathogenic fungi such as sesame leaf blight fungus and wilt fungus, Bacillus subtilis, athlete's foot fungus and Escherichia coli. Therefore, it is useful as a fungicide. Particularly, as the nitrothiophene compound represented by the general formula (1), at least one of the substituents X ₁ , X ₂ and X ₃ is a hydrogen atom, an alkyl group or a haloalkyl group, and at least one of X ₄ and X ₅ is a hydrogen atom Are preferable because they exhibit high antibacterial activity.

Further, the nitrothiophene compound of the present invention can be widely applied to various pathogenic bacteria belonging to, for example, basidiomycetes, fungi, ascomycetes, incomplete fungi, bacteria, and the like. It is also effective against molds. Therefore, the nitrothiophene compound according to the present invention can be an excellent fungicide.

The form of use of the nitrothiophene compound represented by the general formula (1) of the present invention is not particularly limited, and a form of use of a known fungicide can be used as it is.

For example, using an inert solid carrier, a liquid carrier, an emulsifying dispersant, or the like, in any dosage form such as granules, powders, emulsions, wettable powders, flowables, tablets, aerosols, and smokers. Can be. Of course, for example, a spreading agent, a diluent, a surfactant and the like can be appropriately compounded as auxiliary agents in the preparation.

〔Example〕

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Example 1 Method for producing 3- (3-pyridyloxy) -2-nitrothiophene 3-bromo-2-nitrothiophene (1.04 g), 3-
Potassium hydroxide (0.36 g) was added to a solution of hydroxypyridine (0.48 g) and 20 ml of N, N-dimethylformamide, and the mixture was stirred at room temperature for 12 hours.

After completion of the reaction, the reaction solution was added to water, and the generated solid was collected by filtration. The obtained solid was recrystallized from methylene chloride to obtain the desired product (0.77 g).

As a result of an IR measurement of this product is as shown in FIG. 1, absorption based on the nitro group in 1540 and 1340cm ^-1, 1210cm ^-1
Showed strong absorption based on the bond (C-O-C) to the ether. Its elemental analysis values were: C48.46%, H2.70%, N12.47
%, Which is a calculated value corresponding to the composition formula C ₉ H ₆ O ₃ S.
It was in good agreement with 8.65%, H2.72% and N12.61%. When MS was measured, the peak corresponding to M ⁺ was found at m / e222, and m / e176
Peak corresponding to [M ⁺ -NO ₂ ], m / e128 The respective peaks corresponding to are shown. In addition, ¹ H-NMR (δ ppm:
FIG. 2 shows the results of measurement of tetramethylsilane based on deuterated chloroform solvent). The analysis results were as follows.

Double line corresponding to a single proton in 6.59ppm was observed, it could be assigned to be due to protons H _e. 7.11 to 7.51
A multiplet corresponding to three protons is found in ppm,
It could be attributed to protons _Hc , _Hd and _Hb . 8.21-8.
Multiplet corresponding to two pieces of protons observed in 91 ppm, was assigned to be due to protons H _a, H _f.

The above results revealed that the isolated product was 3- (3-pyridyloxy) -2-nitrothiophene (Compound No. 1). The yield was 69.3%.

Example 2 Method for producing 3- (2-methyl-5-pyridyloxy) -2-nitrothiophene 3-bromo-2-nitrothiophene (1.04 g), 2-methyl-5-hydroxypyridine (0.55 g) and N Potassium hydroxide (0.36 g) was added to a solution consisting of N, dimethylformamide (20 ml) and stirred at room temperature for 12 hours.

After completion of the reaction, the reaction solution was added to water, and the generated solid was collected by filtration. The obtained solid was recrystallized from methylene chloride to obtain the desired product (0.83 g).

The result of IR measurement of this product is as shown in FIG. 3, where strong absorption based on a nitro group was observed at 1549 and 1320 cm ⁻¹ ,
The absorption based on the ether bond (C-O-C) was shown at cm ^-1 . Its elemental analysis values are: C50.61%, H3.33%, N11.73%
Is a calculated value corresponding to the composition formula C ₁₈ H ₈ N ₂ O ₃ S C5
0.84%, H3.41% and N11.86% agreed well. When MS was measured, the peak corresponding to M ⁺ was found at m / e236, m / e190
Peak corresponding to [M] ⁺ NO ₂ ], m / e128 The respective peaks corresponding to are shown. In addition, ¹ H-NMR (δ ppm:
FIG. 4 shows the result of measurement of tetramethylsilane standard (deuterated chloroform solvent). The analysis result was as follows.

A single line corresponding to three protons was observed at 2.54 ppm, which corresponded to the methyl proton in (a). Double line corresponding to a single proton in 6.52ppm were observed, it can be assigned to be due to protons H _e. A multiplet corresponding to three protons was observed at 7.15 to 7.55 ppm, and protons H _c ,
H _d, can be attributed to be due to H _b. A broad single line corresponding to one proton was observed at 8.25 to 8.45 ppm,
It can be assigned to be due to protons H _a.

From the above results, the isolated product was 3- (2-methyl-
5-pyridyloxy) -2-nitrothiophene (Compound No. 2). The yield was 70.3%.

Example 3 Various compounds represented by the following general formulas were synthesized in the same manner as in Examples 1 and 2 (Compound Nos. 3 to 6).
6).

(However, X _{1 to} X ₅ are described in Table 1. In addition, the number described before the group in the table indicates a bonding position.) Further, MS, IR and elemental analysis of the synthesized compound are shown in Table 1. Also described.

The bonding position in the table is The position connected to Indicates the position of the bond.

Furthermore, the abbreviations in Table 1 are as follows.

Et; ethyl group, n-Pr; normal propyl group, iso-Pr;
Isopropyl group, ter-Bu; tertiary butyl group.

Application example 1 After sterilizing a nutrient medium containing 1.5% agar by heating at 121 ° C for 15 minutes, cool it to 50 ° C, put the cells or spores grown in advance in sterile water, The mixture was mixed well, poured into a petri dish, and fixed on a flat plate. 15% of the compound synthesized in Example 1, Example 2, Example 3 and Example 4
Circular paper having a diameter of 8 mm was immersed in the contained methanol solution, the excess was removed on the paper, and then placed on a solidified agar medium. After culturing at about 30 ° C. for 24-48 hours, the diameter of the inhibition circle was measured, and the test results are shown in Table 2.

In addition, all the test bacteria in Table 2 are indicated by abbreviations, and those having no effect or those not tested are indicated by-.

Commercially available bacitac was used as a control. Test bacterium or fungus: Escherichia coli
li B: EC), Batillus subtili
s: BS), Aspergillus niger:
AN), Cochlioblus miabaenas (Cochlioblus mi)
yabeanus: CM), Trichophyton Rubram (Trichophy)
tonrubrum: TR), Fusarium oxysporum (Fusari)
um oxyaporum: FO).

[Brief description of the drawings]

Figure 1 is an infrared absorption spectrum of Compound 1, FIG. 2 ¹ H-NMR spectrum of compound 1, Figure 3 is an infrared absorption spectrum of Compound 2, Figure 4 is the ¹ Compound 2 H- It is an NMR spectrum figure.

Claims (1)

(57) [Claims] (1) General formula (However, X ₁ , X ₂ , X ₃ , X ₄ and X ₅ represent a hydrogen atom, a halogen atom, a formyl group, a nitro group, a cyano group, a hydroxyl group,
Alkoxy group, alkylthio group, dialkylamino group,
It represents a different or similar group selected from an alkoxycarbonyl group, a substituted or unsubstituted alkyl group, a monoalkylamino group, an alkenyl group and an alkynyl group, and a substituted or unsubstituted phenyl group. A nitrothiophene compound represented by the formula: