JP2856840B2 - Thienyloxyphenoxycarboxylic acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides a novel thienyloxyphenoxycarboxylic acid derivative useful as a fungicide.

[Problems to be solved by conventional technology and invention]

Hitherto, various examples of synthesis of nitrothiophene compounds in which another organic residue is bonded to a nitrothiophene ring via an ether group have been reported. Example: Annaless. Kimika [Ann. Chem. (Rome), 54: 281, 1964] describes a compound represented by the following general formula (A).

(However, R represents a group selected from a hydrogen atom, a methyl group, a chlorine atom and a bromine atom.) In addition, Journal of American Chemical Society [J. Amer. Chem. Soc. 74, 2965, 1952] describes a compound represented by the following general formula (B).

(However, Represents an alkali group or a phenyl group. However, none of these documents describes the bactericidal / fungicidal activity of nitrothiophenyl compounds, and the present inventors have examined the possibility of these compounds as fungicidal and fungicide agents. Was rarely observed.

[Means for solving the problem]

Therefore, the present inventors have studied the synthesis of a novel thienyloxyphenoxycarboxylic acid derivative represented by the following general formula (1) and the fungicidal / fungicidal activity.

As a result, the thienyloxyphenoxycarboxylic acid derivative represented by the general formula (1) shows a very strong bactericidal / fungicidal effect even when compared with a commercially available bactericidal / fungicidal agent described below, and shows the general formula ( It has been confirmed that the thienyloxyphenoxycarboxylic acid derivative 1) can be a promising fungicide, and the present invention has been completed.

That is, the present invention provides a compound represented by the general formula (1): A thienyloxyphenoxycarboxylic acid derivative represented by the formula:

In the present invention, in the general formula (1), X ₁ , X ₂ , X ₃ ,
Specific examples of the halogen atom represented by X ₄ is chlorine, bromine, fluorine and iodine atoms. In the general formula (1), the alkyl residue represented by X ₁ or X ₂ in the alkoxy group, alkylthio group, alkoxycarbonyl group, monoalkylamino group or dialkylamino group has 1 to 1 carbon atoms.
Four straight or branched ones are preferably used.

Specific examples of the alkyl residue include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl and the like.

Specific examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an iso-propoxy group, an n-butoxy group, an iso-butoxy group, and a tert-butoxy group.

Specific examples of the alkylthio group include a methylthio group, an ethylthio group, an n-propylthio group, an iso-propylthio group, an n-butylthio group, an iso-butylthio group, and a tert-butylthio group.

Specific examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an iso-propoxycarbonyl group, an n-butoxycarbonyl group, an iso-butoxycarbonyl group, and tert.
-Butoxycarbonyl group and the like.

Specific examples of the monoalkylamino group include a methylamino group, an ethylamino group, an n-propylamino group, an iso-
Examples include a propylamino group, an n-butylamino group, an iso-butylamino group, and a tert-butylamino group.

Specific examples of the dialkylamino group include a dimethylamino group, a diethylamino group, a di-n-propylamino group,
Di-iso-propylamino group, di-n-butylamino group, 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-butylamino group, n-propyl-n-butylamino group and the like.

In the general formula (1), as the alkyl group represented by X ₁ , X ₂ , X ₃ , X ₄ , R ¹ , R ² , R ³ and R ⁴ , a linear or linear alkyl group having 1 to 4 carbon atoms Branched ones are preferably used.

Specific examples of the alkyl group include a methyl group, an ethyl group, n
-Propyl group, iso-propyl group, n-butyl group, iso-
Butyl group, tert-butyl group and the like.

In the above general formula (1), the substituents of the substituted alkyl groups represented by X ₁ , X ₂ , X ₃ , X ₄ , R ¹ , R ² , R ³ and R ⁴ are all or all of the hydrogens in the alkyl groups. Those partially substituted with a halogen atom, an alkoxy group, an alkylthio group, a cyano group or the like are preferable.

Specific examples of the substituted alkyl group include chloromethyl, bromomethyl, fluoromethyl, iodomethyl, dichloromethyl, chlorodifluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, methoxymethyl, Ethoxymethyl, methylthiomethyl, cyanomethyl, chloroethyl, bromoethyl, fluoroethyl, dichloroethyl, dibromoethyl, difluoroethyl, trichloroethyl, trifluoroethyl, perfluoroethyl, perfluoropropyl Groups, methoxyethyl groups, ethoxyethyl groups, methoxypropyl groups, methylthioethyl groups, ethylthioethyl groups, cyanoethyl groups, cyanopropyl groups, and the like.

In the above formula (1), the alkenyl group represented by X ₁ , X ₂ , R ² and R ³ is preferably a linear or branched one having 1 to 4 carbon atoms.

Specific examples of the alkenyl group include a vinyl group, an allyl group,
Examples thereof include a propenyl group, a 2-butenyl group, and a 3-butenyl group.

In the above general formula (1), the alkynyl group represented by X ₁ , X ₂ , R ₂ , and R ₃ is preferably a linear or branched one having 1 to 4 carbon atoms.

Specific examples of the alkynyl group include an ethynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, and a 3-butynyl group.

In the above general formula (1), as the substituted phenyl group represented by R ¹ , one or more hydrogen atoms on the aromatic ring are different or the same kind of a halogen atom, an alkyl group, an alkoxy group, an alkylthio group, a cyano group. Those substituted with a group, an alkoxycarbonyl group and the like are preferred. Specific examples of such a substituted phenyl group include chlorophenyl, bromophenyl, fluorophenyl, iodophenyl, dichlorophenyl, trichlorophenyl, chloro-methylphenyl, bromo-phenyl, and chloroethylphenyl. A chloro-cyanophenyl group, a chloro-methoxycarbonylphenyl group, a methyl-ethylphenyl group,
Trimethylphenyl group, cyanotolyl group, methylthiotolyl group, trimethoxyphenyl group, tetrachlorophenyl group, chloro-dimethylphenyl group, methoxyphenyl group, ethoxyphenyl group, isopropoxyphenyl group,
Ethylthiophenyl group, dichloro-cyanophenyl group,
And a dichloro-ethoxycarbonylphenyl group.

The structure of the thienyloxyphenoxycarboxylic acid derivative represented by the general formula (1) of the present invention can be confirmed by the following means.

(A) By measuring the infrared absorption spectrum (IR), it was found that the absorption based on the ether bond was around 1250 to 1200 cm ^-1 ,
40～1510Cm ^-1 and 1350～1320Cm ^-1 near the absorption based on the nitro group, can be observed a characteristic absorption based on 1600～1500Cm ^-1 Fukinru aromatic ring. As a representative example, 2- [P- (2
FIG. 1 shows the infrared absorption spectrum of ethyl -nitro-3-thienyloxy) phenoxybutyrate.

(B) By measuring a mass spectrum (MS) and calculating a composition formula corresponding to each observed peak (generally, the number represented by m / e divided by the number of charges e of the ion having an ion molecular weight of m), It is possible to know the molecular weight of the compound subjected to the measurement and the bonding mode of the atomic groups in the molecule. That is,
The sample subjected to the measurement is represented by the general formula (1) In general, the molecular ion peak (hereinafter abbreviated as M ⁺ ) is measured at an intensity according to the isotope abundance ratio according to the number of halogen atoms contained in the molecule, and therefore, the compound subjected to the measurement is used. Can be determined. Also,
For the compound represented by the general formula (1), A characteristic peak corresponding to the above is observed, and the binding mode of the molecule can be known.

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.
X ₁ , X ₂ , X ₃ , X ₄ , R ¹ , R ² , R ³ R ^{4 in the} aforementioned general formula (1)
Regardless of the type, protons such as thiophene rings are 6.0-
It generally appears as a multiline at around 8.5 ppm.

As a representative example of ¹ H-NMR (δ ppm: tetramethylsilane standard, deuterated chloroform solvent) of the compound, ethyl 2- [p-nitro-3-thienyloxy) phenoxy] butyrate was used.
^{The 1} H-NMR diagram is shown in FIG. The analysis results are as follows.

That is, double line was observed corresponding to a single proton in 6.43Ppm, it can be assigned to be due to protons H _a. 7.31
A double line corresponding to one proton is recognized in ppm,
This could be attributed to the proton _Hb . Multiplet was observed corresponding to 4 pieces of the proton 6.65～7.16Ppm, was assigned proton _{H c, H d, H e} , and by H _f. Triplet is observed corresponding to a single proton in 4.50Ppm, it can be assigned to be due to protons H _g.

A triplet corresponding to three protons was found at 1.07 ppm, which could be attributed to the methyl proton (a).
A triplet corresponding to three protons was observed at 1.24 ppm, which could be attributed to the methyl proton (b).

A multiplet corresponding to two protons was observed at 1.65 to 1.86 ppm, which could be attributed to the methylene proton (c). A quadruple corresponding to two protons was observed at 4.20 ppm, which could be attributed to the methylene proton (d).

(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 thienyloxyphenoxycarboxylic acid derivative 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 soluble in organic solvents such as acetone, N, N-dimethylformamide and dimethylsulfoxide, but is insoluble or hardly soluble in water.

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

Examples of typical production methods include: (a) general formula (2), [However, X ₅ represents a halogen atom, and X ₁ and X ₂ are as shown in the general formula (1). The halogenothiophene compound represented by the general formula (3) [However, M represents a hydrogen atom or an alkali metal, and X ₃ ,
X ₄ , R ¹ and Y are as shown in the general formula (1). With a phenol derivative represented by the formula (4): [However, M represents a hydrogen atom or an alkali metal, and X ₁ ,
X ₂ , X ₃ , and X ₄ are as shown in the general formula (1). The thienyloxyphenol compound represented by the general formula (5) (Wherein X ₅ represents a halogen atom, and R ¹ and Y are as shown in the general formula (1)). The compound can be produced by reacting with a halogenocarboxylic acid derivative of the formula (1) in the presence or absence of a solvent. .

In the above reaction (a), the charged molar ratio of the halogenothiophene compound represented by the general formula (2) and the phenol derivative represented by the general formula (3) may be appropriately determined as necessary, but may be usually determined. It is common to use a slight excess of the molar or phenol derivative.

In the above reaction (b), the charged molar ratio of the halogenocarboxylic acid derivative represented by the general formula (5) and the thienyloxyphenol compound represented by the general formula (4) may be appropriately determined as necessary. It is common to use an equimolar or slightly excess thienyloxyphenol compound.

In general, benzene, toluene, xylene, methylene chloride, chloroform, N, N-dimethylformamide and the like are suitably used as the solvent for the reactions (a) and (b). In addition, in the reactions (a) and (b), when M is a hydrogen atom, it is usually preferable to coexist a hydrogen halide scavenger in the reaction system in order to capture by-produced hydrogen halide. The hydrogen halide scavenger is not particularly limited, and a known one can be used. As the hydrogen halide scavenger, trialkylamines such as triethylamine, trimethylamine and tripropylamine are generally preferred.
Pyridine; sodium alcoholate; sodium carbonate;
Potassium carbonate; sodium hydroxide; potassium hydroxide; sodium hydroxide and the like.

Also, in the reactions (a) and (b), the hydroxythiophene compound represented by the general formula (3) and the general formula (4)
As the alkali metal of the hydroxypyridine compound represented by the formula, sodium, potassium and lithium can be used, but sodium and potassium are generally preferred.

The reaction temperature of the reactions (a) and (b) is usually from room temperature to 200 ° C.
The temperature is preferably in the range of room temperature to 150 ° C. The reaction time is from 0.5 to 80 hours, preferably from 8 to 15 hours.

The method for isolating and purifying the thienyloxyphenoxycarboxylic acid derivative 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, the generated solid is separated by filtration, and the solid is purified by recrystallization or column chromatography, or, if the solvent is not mixed with water, the reaction solution is added to water, and the organic solvent is added. , The solvent is distilled off, and the residue is preferably recrystallized or purified by column chromatography.

(Effect)

The thienyloxyphenoxycarboxylic acid derivative represented by the general formula (1) of the present invention can be used against plant pathogenic fungi such as sesame leaf blight fungus and wilt fungus, fungi such as Bacillus subtilis, Escherichia coli, and molds such as athlete's foot fungi. Since it has strong antibacterial activity, it is useful as a fungicide. In particular, compound numbers (4), (5), and thienyloxyphenoxy carboxylic acid derivatives having high antibacterial activity described in Examples.
There are compounds such as (6) and (7). Therefore, the thienyloxyphenoxycarboxylic acid derivative represented by the above-mentioned one formula (1) can be an excellent fungicide.

The use form of the thienyloxyphenoxycarboxylic acid derivative represented by the general formula (1) of the present invention is not particularly limited, and the use form of a known fungicide / fungicide can be used as it is. For example, using an inert solid carrier, a liquid carrier, an emulsifying dispersant, and the like, granules, powder, milk, wettable powder, flowable,
It can be used in any dosage form such as tablets, aerosols, smoke agents and the like. Of course, for example, a spreading agent, a diluent, a surfactant and the like can be appropriately blended and used as an auxiliary 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 ethyl 2- [p- (2-nitro-3-thienyloxy) phenoxy] butyrate Ethyl 2- [p-hydroxyphenyloxy] butyrate (2.24 g), 2-nitro-3-bromothiophene ( 2.08
g) and 20 ml of N, N-dimethylformamide were added with potassium hydroxide (0.73 g) 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 (3.10 g).

As a result of an IR measurement of the thigh is as shown in FIG. 1, absorption based on the nitro group in 1552 and 1328cm ^-1, 1200 cm ^-1
Strong absorption based on ether bond (C-O-C), 173c
m- ₁ showed an absorption based on a carbonyl group. Its elemental analysis values were: C: 54.50%, H: 4.89%, N: 4.00%.
Is a calculated value corresponding to _{C 16 H 17 NO6S C54.69%,} H4.88
%, N3.99%. When MS was measured, the peak corresponding to M ⁺ was found at m / e351, and (M ⁺ -COOC was found at m / e278.
₂ H ₅ ), m / e223 The respective peaks corresponding to are shown. FIG. 2 shows the results of measurement of ¹ H-NMR δ ppm: tetramethylsilane standard, deuterated chloroform solution). The analysis result was as follows.

Double line corresponding to a single proton in 6.43ppm was observed, it could be assigned to be due to protons H _a. At 7.31 ppm, a double line corresponding to one proton was recognized, which could be attributed to the proton _Hb . A multiplet corresponding to four protons was observed at 6.65 to 7.16 ppm, and protons H _c ,
H _d, H _e, could be attributed to be due to H _f. Triplet is observed corresponding to a single proton in 4.50Ppm, was assigned to be due to protons H _g. A triplet corresponding to three protons was found at 1.07 ppm, which could be attributed to the methyl proton (a). A triplet corresponding to three protons was observed at 1.24 ppm, which could be attributed to the methyl proton (b). A multiplet corresponding to two protons was observed at 1.65 to 1.86 ppm, which could be assigned to that due to methylptron (c). A quadruple corresponding to two protons was observed at 4.20 ppm, which could be attributed to the methylene proton (d).

The above results revealed that the isolated product was ethyl 2- [p- (2-nitro-3-thienyloxy) phenoxy] butyrate. The yield was 96.5%.

 This compound was designated as compound number (1).

Example 2 Method for producing ethyl 2- [p- (5-cyano-3-nitro-2-thienyloxy) phenoxy] butyrate Ethyl 2- [p-hydroxyphenyloxy] butyrate (2.38 g), 2-bromo-5 Potassium hydroxide (0.73 g) was added to a solution of -cyano-3-nitrothiophene (2.33 g) and N, N-dimethylformamide (20 ml), 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 (3.12 g).

The result of IR measurement of this product is shown in FIG. 3, where absorptions at 1540 and 1320 cm ⁻¹ based on a nitro group were observed and 1230 cm ^−1.
Strong absorption based on ether bond (COC), 1740
The absorption based on the nitrile group was shown at cm ^-1 . Its elemental analysis values were C54.15%, H4.40%, and N7.50%.
₁₇ H ₁₆ N ₂ O ₆ is a calculated value corresponding to the S C54.25%, H4.28
%, N7.44%. When MS was measured, the peak corresponding to M ⁺ was found at m / e376, and (M ⁺ -COOC
₂ H ₅ ) peak at m / e223 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.

Singlet corresponding to a single proton in 7.90ppm was observed, it could be assigned to be due to protons H _a. Triplet is observed corresponding to a single proton in 4.58Ppm, was assigned to be due to protons H _f. Double line was observed corresponding to the two partial proton 6.91Ppm, it was assigned proton H _d, to be due to H _e. Double lines corresponding to two pieces of protons observed 7.70Ppm, was assigned to be due to protons H _b, H _c. A multiplet corresponding to two protons was observed at 1.68 to 2.31 ppm, which was attributed to the methylene proton (C). A triplet corresponding to three protons was observed at 1.11 ppm, which could be attributed to the methyl proton (a). A triplet corresponding to three protons was observed at 1.29 ppm, which could be assigned to that due to methyleneptron (b). A quadruple corresponding to two protons was observed at 4.24 ppm, which could be attributed to the methyl proton (d).

From the above results, the isolated product was 2- [p- (5-cyano-3-nitro-2-thienyloxy) phenoxy]
It was found to be ethyl butyrate. 80.0% yield
Met.

 The compound was designated as compound number (2).

Example 3 Various compounds represented by the following general formulas were synthesized in the same manner as in Examples 1 and 2.

(However, X _{1 to} X ₄ and Y are described in Table 1).
Table 1 also shows MS, IR and elemental analysis of the synthesized compound.

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

Example 4 Various compounds represented by the following general formulas were synthesized in the same manner as in Examples 1 and 2.

(However, X _{1 to} X ₄ and Y are described in Table 2). Table 2 also shows MS, IR and elemental analysis of the synthesized compound.

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

Example 5 Various compounds represented by the following general formulas were synthesized in the same manner as in Examples 1 and 2.

(However, X1 to X4 and Y are described in Table 3). Table 3 also shows MS, IR and elemental analysis values of the synthesized compound.

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

Application Example 1 A nutrient medium containing 1.5% agar is heat-sterilized at 121 ° C. for 15 minutes, cooled to 50 ° C., and grown in advance and a suspension of cells or spores in sterile water is added. 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
A circular paper having a diameter of 8 mm was immersed in the contained methanol solution, and the excess was removed on the paper, and then placed on a solidified agar plate. 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 4.

The test bacteria in Table 4 are all indicated by abbreviations, and those having no effect or not tested are indicated by-.

As a control, commercially available Vashitac was used. As test bacteria or fungi: Escherichia coli B (Escher
ichia colli B: EC), Bacillus subtilis (Batillus)
subtills: BS), Aspergillus niger
s: AN), Cochliobolus miyabenas (Cochliobolus)
miyabeanus: CM) Trichophyton Rubram (Tricho)
phytonrubrum: TR), Fusarium oxysbolum (Fus)
arium oxyaporum: FO).

[Brief description of the drawings]

FIG. 1 shows the infrared spectrum of the compound (Compound No. (1)) obtained in Example 1, and FIG. 2 shows the ¹ H-NMR spectrum of the compound (Compound No. (1)) obtained in Example 1. the compound Figure 3 is obtained in example 2 the infrared spectrum (compound (2)), ¹ H- compound of Fig. 4 obtained in example 2 (compound No. (2)) Each NMR spectrum is shown.

Claims (1)

(57) [Claims] (1) General formula A thienyloxyphenoxycarboxylic acid derivative represented by the formula: