JP3127386B2 - Amino acid amide derivatives and fungicides for agricultural and horticultural use - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel compound, an amino acid amide derivative, which has not been described in any literature, and a fungicide for agricultural and horticultural use containing the same as an active ingredient.

[0002]

Heretofore, N 1 ^- [1- (2- furanyl) ethyl] -N 2 ^- amino acid amide derivatives such as phenoxycarbonyl -L- valinamide is known to be useful as pesticides (Japanese Patent Laid-Open No. 3-153
657 publication). ^Further, N 1 - [1- (2- benzo [b] thienyl) ethyl] -N ² - benzyloxycarbonyl -L- ^valinamide, N 2-tert-butoxycarbonyl ^-N 1 - [1- (3- chloro - Amino acid amide derivatives such as [2-benzofuranyl) ethyl] -L-valinamide are known to be useful as fungicides (EP 587110).

[0003]

On the other hand, when a bactericide is used repeatedly, a resistant bacterium against the drug may appear and may not show sufficient bactericidal activity. In addition, due to environmental problems, a bactericide can be efficiently harmful at a low concentration. There is a need for new fungicides that can control bacteria.

[0004]

Means for Solving the Problems The present inventors have synthesized various amino acid amide derivatives in order to develop a drug having a bactericidal activity superior to known bactericides, and examined the physiological activity. The compound of the present invention, which binds a benzothiazole ring, a benzoxazole ring or a benzimidazole ring to the amine moiety, has a wide range of bactericidal spectrum at a low dose, especially tomato blight, potato blight, grape downy mildew, cucumber downy mildew The present invention has been found to have excellent bactericidal activity and to have no harm to useful crops, and to complete the present invention.

That is, the present invention provides (1) a general formula

[0006]

Embedded image [In the formula, R ^1, Cl to 6 alkyl, C3-8 cycloalkyl group, a phenyl group (the phenyl group may be substituted one or more places in the same or different <br/> different halogen atoms ) Or a benzyl group; R ² represents a hydrogen atom or a methyl group; X represents a halogen atom, a methyl group, a methoxy group, a methylthio group, a cyano group or a trifluoromethyl group; 6 represents an alkyl group, A represents an oxygen atom, a sulfur atom or a group> NR ³ (R ³ represents a C1-6
A kill group, a C1-6 alkoxymethyl group or an acyl group . ) And n represents 0 or an integer of 1 to 3. (2) A fungicide for agricultural and horticultural use containing these amino acid amide derivatives as an active ingredient.

[0007] The definitions of terms used in this specification are shown below.

The term "alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. Group, tert-butyl group, pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 2,2-dimethylpropyl group, 1,1-dimethylpropyl group, 1-ethylpropyl group, hexyl group, Examples include an isohexyl group.

The halogen atom means a fluorine atom, chlorine atom, bromine atom, iodine atom and the like. The cycloalkyl group refers to a cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cycloheptyl group, and a cyclooctyl group.

The term "alkoxymethyl group" means a straight-chain or branched-chain alkoxymethyl group having 1 to 6 carbon atoms, such as a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, an isopropoxymethyl group and a butoxymethyl group. , Isobutoxymethyl group, sec-butoxymethyl group and the like.

The acyl group means an acetyl group, a benzoyl group or the like.

The compound of the present invention represented by the general formula [I]
Having one or two asymmetric carbon atoms in the molecule, these compounds can be resolved in any suitable way. Various diastereomers and enantiomers exist, and pure individual diastereomers, enantiomers and mixtures thereof are also included in the compounds of the present invention.

In the general formula [I], preferred compounds are those in which R ¹ is a linear or branched alkyl or phenyl group having 2 to 6 carbon atoms, R ² is a hydrogen atom or a methyl group, and X is Compounds in which a halogen atom, Y is an isopropyl group, A is a sulfur atom, n is 0 or 1, and the amino acid is L-form can be mentioned. Particularly preferred compounds are N ¹ -[(R) -1- (6-fluoro-2-
Benzothiazolyl) ethyl] -N ² - is isopropoxycarbonyl -L- valinamide.

Next, typical examples of the compound of the present invention represented by the general formula [I] are shown in Tables 1 to 6, but are not limited thereto. The compound numbers will be referred to in the following description.

[0015]

[Table 1]

[0016]

[Table 2]

[0017]

[Table 3]

[0018]

[Table 4]

[0019]

[Table 5]

[0020]

[Table 6]

In Tables 1 to 6, the configuration of the amino acid portion (* ¹ ) of the compound is such that only Compound 35 is in the DL form,
Other compounds are in L-form. The configuration of the other asymmetric carbon (* ² ) is as follows: Compounds 3 to 4, Compounds 6 to 1
2, Compounds 17 to 21, Compound 23, Compound 32, and Compound 111 are R-forms, and Compound 5, Compounds 13 to 14,
Compound 22, Compounds 24-31, 34-41, 43-48, 51-67, 69, 71-73, 75-77, 79-81,
Compound 83 to 94, Compound 96 to 98, Compound 100 to
103, compounds 105-107, compounds 109-11
0, Compounds 112 to 117 are RSs.

The compound of the present invention represented by the general formula [I]
For example, it can be manufactured according to the following manufacturing method. Manufacturing method A

[0023]

Embedded image (In the formula, R ¹ , R ² , X, Y, A and n have the same meaning as described above.)

The compound [I] of the present invention can be prepared by reacting an amino acid derivative represented by the general formula [II] or a derivative having its carboxyl group activated, if necessary, in the presence of a catalyst and / or a base. III] to react with the amines.

In this reaction, examples of the derivative in which the carboxyl group of the amino acid derivative represented by the general formula [II] is activated include acid halides such as acid chlorides and amino acids represented by the general formula [II] An acid anhydride obtained by dehydration-condensation of two molecules of a derivative, a mixed acid anhydride composed of an amino acid derivative represented by the general formula [II] and another acid or O-alkyl carbonate, p-nitrophenyl ester, Activated esters such as tetrahydropyranyl ester and 2-pyridyl ester can be exemplified.

This reaction can also be carried out using a condensing agent such as N, N'-dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium chloride.

This reaction is usually performed in a solvent. As a solvent that can be used, any solvent that does not inhibit the reaction may be used, for example, pentane, hexane, heptane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene and other hydrocarbons, dichloromethane, dichloroethane, chloroform, tetrachloride Carbon, chlorobenzene, halogenated hydrocarbons such as dichlorobenzene, ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone,
Ketones such as methyl isopropyl ketone and methyl isobutyl ketone; acetates such as methyl acetate and ethyl acetate; nitriles such as acetonitrile, propionitrile and benzonitrile; and dimethyl sulfoxide, N,
An aprotic polar solvent such as N-dimethylformamide and sulfolane and a mixed solvent obtained by combining solvents selected from these can be used.

As the base, all generally used in this type of reaction can be used. For example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and triethylamine, trimethylamine, N, N-dimethylaniline, pyridine, N-methylpiperidine, 1,5
-Diazabicyclo [4.3.0] non-5-ene (DB
N), organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and the like, and preferably tertiary amines such as triethylamine, pyridine and N-methylpiperidine. Is mentioned.

As the catalyst, for example, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, N,
N-dimethylformamide and the like.

The reaction temperature ranges from -75 ° C to 100 ° C.
It is preferably carried out in the range of -60C to 40C.
The reaction time is preferably 1 to 20 hours.

Next, a method for producing a starting compound used in this production will be described.

First, the compound represented by the general formula [II] is
For example, by reacting L-valine with di (tert-butyl) dicarbonate in the presence of sodium hydrogen carbonate,
It can be produced as N-tert-butoxycarbonyl-L-valine. Also, by reacting DL-valine with carbobenzoxycyclolide in the presence of sodium hydrogen carbonate, N-benzyloxycarbonyl-D
It can be manufactured as L-valine. These are already known methods [Methoden der Organischen Chemi
e), Volume 15, Issue 2, Page 2; Georg Chime
Georg Thieme Verlag St
uttgart) (1974); Chemistry of the
Amino Acids (Chemistry of the Amino Acids),
Vol. 2, p. 891, John Wiley & Sons, NY (19)
64); Journal of the American Chemical Society
Society, Vol. 79, p. 4686 (1957)
Year)〕.

Among the raw material compounds in which the carboxyl group of the amino acid derivative is activated, for example, a mixed acid anhydride is obtained by converting the amino acid derivative represented by the general formula [II] and pivaloyl chloride in the presence of an organic base. Can be produced by reacting The p-nitrophenyl ester can be produced by reacting the amino acid derivative represented by the general formula [II] with p-nitrophenol in the presence of a condensing agent.

These are already known methods [Methoden del Organischen Chemie
der Organischen Chemie), Vol. 15, No. 2, No. 2
P .; Georg Thieme Verlag Stuttgart (1974);
Chemische Berichte, 38
Vol. 605 (1905); Journal of the American Chemical Society (Journal of t.)
he American Chemical Society), Vol. 74, 676
Page (1952); Journal of the American Chemical Society
Chemical Society), Vol. 86, p. 1839 (196
4 years)].

The fused heterocyclic derivative represented by the general formula [III] can be produced, for example, according to the following reaction formula. Raw material production method A

[0036]

Embedded image (In the formula, X, A and n have the same meaning as described above.)

Compound [III] can be produced according to the following reaction formula. Raw material production method B

[0038]

Embedded image (Wherein, R ² , X, A and n have the same meaning as described above, R ³ represents a hydrogen atom or an alkyl group, and Ac represents
Indicates an acetyl group. ) Raw material production method C

[0039]

Embedded image (In the formula, R ² , X, A and n have the same meaning as described above.)

The compound represented by the general formula [III] is a compound in which the amino group of the amino acid represented by the general formula [VIII] is protected or the compound whose carboxyl group is activated, if necessary, a catalyst and And / or by reacting with an aniline represented by the general formula [IX] in the presence of a base, and then removing the amino protecting group of the amino acid. For this removal, a widely known method, for example, a catalytic reduction method or a method of treating with liquid hydrogen fluoride, sulfonic acids, hydrogen chloride, hydrogen bromide, formic acid, or another acid can be used. Raw material production method D

[0041]

Embedded image (Wherein, R ² , X and n have the same meaning as described above;
Represents a sulfur atom. )

The compound represented by the general formula [III-1]
A compound in which the amino group of the amino acid represented by the general formula [VIII] is protected or a compound in which the carboxyl group is activated is represented by the general formula [X] in the presence of a catalyst and / or a base, if necessary. , And then reducing with a reducing agent, and further removing the amino protecting group of the amino acid.
For this removal, a widely known method, for example, a catalytic reduction method or a method of treating with liquid hydrogen fluoride, sulfonic acids, hydrogen chloride, hydrogen bromide, formic acid or the like can be used.

In these raw material production methods, the general formula [VI
Examples of the amino protecting group of the amino acid represented by II] include urethane-type protecting groups such as tert-butoxycarbonyl group and benzyloxycarbonyl group, acyl-type protecting groups such as formyl group and phthaloyl group, and triphenylmethyl group. And the like.

On the other hand, examples of the compound having an activated carboxyl group include acid halides such as acid chlorides, acid anhydrides obtained by dehydrating and condensing two molecules of the amino acid derivative represented by the general formula [VIII], and the like. Activities of mixed acid anhydrides, p-nitrophenyl esters, 2-tetrahydropyranyl esters, 2-pyridyl esters, etc., composed of a derivative of the amino acid represented by the formula [VIII] and other acids or O-alkyl carbonic acid And the like.

Further, the reaction of the raw material production methods C and D includes N,
It can also be carried out using a condensing agent such as N'-dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium chloride.

Production method B

[0047]

Embedded image ^{{Wherein, R 1, R 2, X} , Y, A and n are as defined above, Z is a halogen atom or a group ^R 1 OC
(O) O- is shown. ｝

The compound [I] of the present invention is obtained by converting a compound represented by the general formula [IV] into an inorganic compound such as an amine represented by the general formula [V] or a hydrochloride thereof, if necessary, in the presence of a base. It can be produced by reacting with an acid salt or an organic acid salt such as a tosylate.

This reaction is usually performed in a solvent. As a solvent that can be used, any solvent that does not inhibit the reaction may be used, for example, pentane, hexane, heptane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene and other hydrocarbons, dichloromethane, dichloroethane, chloroform, tetrachloride Carbon, chlorobenzene, halogenated hydrocarbons such as dichlorobenzene, ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone,
Ketones such as methyl isopropyl ketone and methyl isobutyl ketone; acetates such as methyl acetate and ethyl acetate; nitriles such as acetonitrile, propionitrile and benzonitrile; dimethyl sulfoxide, N, N-dimethylformamide and sulfolane A mixed solvent obtained by combining a protic polar solvent, water and a solvent selected from these can be used.

As the base, all generally used in this type of reaction can be used. For example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, further, triethylamine, trimethylamine, N , N-dimethylaniline, N-methylmorpholine, pyridine, N
-Methylpiperidine, 1,5-diazabicyclo [4.
3.0] non-5-ene (DBN), organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), and the like, preferably, triethylamine, N-methyl Tertiary amines such as morpholine, pyridine, and N-methylpiperidine.

The reaction temperature ranges from -20 ° C to 100 ° C, preferably from -20 ° C to 40 ° C. The reaction time is preferably 30 minutes to 20 hours.

Next, a method for producing the starting compound used in this production will be described.

The fused heterocyclic derivative represented by the general formula [V] can be obtained by, for example, removing the amino protecting group of an amino acid from a carbamic acid ester of the compound [I] synthesized by the production method A. For example, by a catalytic reduction method or treatment with an acid such as liquid hydrogen fluoride, sulfonic acids, hydrogen chloride, hydrogen bromide, or formic acid.

The compound represented by the general formula [IV]
For example, it can be produced from the corresponding alcohols or phenols and phosgene.

Next, a production example of the starting compound represented by the general formula [III] will be described. Reference Example 1 Production of (R, S) -1- (5-fluoro-2-benzimidazolyl) ethylamine 2-acetyl-5-fluorobenzimidazole 31.
4 g was dissolved in 500 ml of methanol, and 135.8 g of ammonium acetate and 7.8 g of sodium cyanoborohydride were added thereto, followed by stirring at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, made acidic with concentrated hydrochloric acid, and extracted with diethyl ether. The obtained aqueous layer was made alkaline with a 5% aqueous sodium hydroxide solution and extracted with ethyl acetate. After the organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 6.2 g of the desired product (yield: 20).
%).

¹ H-NMR; (CDCl ₃ , δ) 1.57 (3H, d) 4.39 (1H, q) 5.10 (3H, bs) 7.08 to 7.52 (3H, m)

Reference Example 2 (R) -1- (4-chloro-2)
Preparation of -benzothiazolyl) ethylamine N-tert-butoxycarbonyl-D-alanine 2
0.5 g was dissolved in 200 ml of tetrahydrofuran, 18.4 g of N, N'-carbonyldiimidazole was added little by little, and the mixture was stirred at room temperature for 30 minutes. 16.5 g of 2-amino-3-chlorothiophenol was added to the reaction solution, and the mixture was refluxed for 3 hours. After the completion of the reaction, the reaction solution was transferred to ice water and extracted with ethyl acetate. After the organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 16.8 g of (R) -N-tert-butoxycarbonyl-1- (4-chloro-2-benzothiazolyl) ethylamine (melting point: 95 to 96 ° C). Furthermore,
10 g of the obtained crystals were dissolved in 50 ml of dichloromethane, and hydrogen chloride gas was blown at room temperature for 3 hours. After completion of the reaction, the reaction solution was extracted with water. The obtained aqueous layer was made alkaline with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 5.7 g of the desired product (yield 84%).

¹ H-NMR; (CDCl ₃ , δ) 1.60 (3H, d) 1.89 (2H, s) 4.55 (1H, q) 7.17 to 7.76 (3H, m)

Reference Example 3 (R) -1- (6-methyl-2)
Preparation of -benzothiazolyl) ethylamine N-tert-butoxycarbonyl-D-alanine 1
2.8 g was dissolved in 100 ml of tetrahydrofuran, 11.5 g of N, N'-carbonyldiimidazole was added little by little, and the mixture was stirred for 30 minutes. 8.9 g of 2-amino-5-methylphenyl disulfide was added to the reaction solution, and the mixture was refluxed for 3 hours. After the completion of the reaction, the reaction solution was transferred to ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Next, the obtained 2- [N- (N'-tert-butoxycarbonyl-D-alanyl)] amino-5-methylphenyldisulfide was dissolved in 100 ml of tetrahydrofuran without purification, and 1.2 g of lithium aluminum hydride was dissolved. Was added little by little, and the mixture was stirred at room temperature for 15 hours.
The reaction was transferred into 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 3 g of (R) -N-tert-butoxycarbonyl-1- (6-methyl-2-benzothiazolyl) ethylamine (melting point: 101 to 104)
° C). Further, the obtained crystals are mixed with 30 m of dichloromethane.
and hydrogen chloride gas was blown in at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off from the reaction solution under reduced pressure. The residue was made alkaline by adding a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.3 g (yield: 11%) of the desired product.

¹ H-NMR; (CDCl ₃ , δ) 1.59 (3H, d) 1.90 (2H, s) 2.42 (3H, s) 4.45 (1H, q) 7.05- 7.90 (3H, m)

Next, a production example of the starting compound represented by the general formula [V] will be described. Reference Example 4 Production of N ¹ -[(R) -1- (2-benzothiazolyl) ethyl] -L-valinamide N ² -tert-butoxycarbonyl-N ¹ -[(R)
0.6 g of -1- (2-benzothiazolyl) ethyl] -L-valinamide was dissolved in 20 ml of dichloromethane, and hydrogen chloride gas was blown at room temperature for 1 hour. After the reaction,
50 ml of water was added to the reaction solution, followed by vigorous stirring. The aqueous layer was made alkaline with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate.
g (100% yield).

¹ H-NMR; (CDCl ₃ , δ) 0.93 (6H, t) 1.59 (2H, s) 1.69 (3H, d) 2.33 (1H, m) 3.28 ( 1H, d) 5.49 (1H, dq) 7.16 to 8.03 (4H, m) 8.13 (1H, bs)

[0063]

Next, the process for producing the compound of the present invention will be described specifically. Production Example ^{1 N 1 - [(R)} -1- (6- fluoro-2-
Benzothiazolyl) ethyl] -N ² - dissolving isopropoxycarbonyl -L- valinamide (Compound No. 4) In a 25ml of dichloromethane to N- isopropoxycarbonyl -L- valine 0.8 g, N- methylpiperidine 0.4 g - It was added at 20 ° C. and stirred at this temperature for 10 minutes. Next, 0.6 mL of isobutyl chloroformate was added to the mixture.
g was added at -20 degreeC, and it stirred at -20 degreeC--10 degreeC for 1 hour. (R) -1- (6-Fluoro-2-
After adding benzothiazolyl) ethylamine (0.8 g) at −60 ° C., the mixture was stirred until the temperature reached room temperature except for the refrigerant. After completion of the reaction, the reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in that order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography to obtain 0.95 g (yield 63%) of a target product as a white powder.

Production Example 2 Production of N ¹ -[(R) -1- (4-chloro-2-benzothiazolyl) ethyl] -N ² -isopropoxycarbonyl-L-valinamide (Compound No. 7) 0.96 g of isopropoxycarbonyl-L-valine was dissolved, 0.5 g of N-methylpiperidine was added at -20 ° C, and the mixture was stirred at this temperature for 10 minutes. Next, isobutyl chloroformate was added to the mixture at 0.
6 g was added at −20 ° C., and the mixture was stirred at this temperature for 30 minutes. After adding 1.0 g of (R) -1- (4-chloro-2-benzothiazolyl) ethylamine to the reaction solution at -60 ° C,
The mixture was stirred at room temperature for 15 hours except for the refrigerant. After completion of the reaction, the reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in that order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography to give 0.35 g of the desired product as a colorless powder.
(19% yield).

Production Example 3 Production of N ² -tert-butoxycarbonyl-N ¹ -[(R) -1- (6-chloro-2-benzothiazolyl) ethyl] -L-valineamide (Compound No. 21) N in 50 ml of dichloromethane 0.8 g of -tert-butoxycarbonyl-L-valine was dissolved, 0.37 g of N-methylpiperidine was added at -20 ° C, and the mixture was stirred at this temperature for 10 minutes. Next, 0.51 g of isobutyl chloroformate was added to the mixture at −20 ° C., and the mixture was stirred at this temperature for 30 minutes. 0.8 g of (R) -1- (6-chloro-2-benzothiazolyl) ethylamine was added to the reaction solution at -60 ° C, and the mixture was stirred at room temperature for 15 hours except for the refrigerant. After completion of the reaction, the reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in that order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography to obtain 1.3 g (yield 87%) of a target product as colorless prism crystals.

[0066] Production Example 4 ^N 2-tert-butoxycarbonyl ^-N 1 - [1- (5- fluoro-2-benzimidazolyl) ethyl] -L- valinamide (Compound No. 2
Preparation of 4) 2.4 g of N-tert-butoxycarbonyl-L-valine was dissolved in 100 ml of dichloromethane, 1.1 g of N-methylpiperidine was added at -20 ° C, and the mixture was stirred at this temperature for 10 minutes. Next, 1.5 g of isobutyl chloroformate was added to the mixture at −20 ° C., and the mixture was stirred at this temperature for 30 minutes. After adding 2.0 g of 1- (5-fluoro-2-benzimidazolyl) ethylamine to the reaction solution at -60 ° C, the mixture was stirred at room temperature for 15 hours except for the refrigerant. After the reaction,
The reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in that order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography, and the target compound was obtained as colorless needle crystals.
5 g (60% yield) was obtained.

[0067] Production Example 5 ^N 1 - [1- (2- benzothiazolyl) ethyl] -N ² - isopropoxycarbonyl -
Production of L-valine amide (Compound No. 31) 0.6 g of N-isopropoxycarbonyl-L-valine was dissolved in 40 ml of dichloromethane, 0.3 g of N-methylpiperidine was added at −20 ° C., and the mixture was stirred at this temperature for 10 minutes. . Next, 0.4 mL of isobutyl chloroformate was added to the mixture.
g was added at −40 ° C., and the mixture was stirred at −40 ° C. to −15 ° C. for 1 hour. After 0.5 g of 1- (2-benzothiazolyl) ethylamine was added to the reaction solution at -60 ° C, the mixture was stirred until the temperature reached room temperature except for the refrigerant. After the reaction, add 5% water to the reaction solution.
After washing with an aqueous sodium hydrogen carbonate solution and water in that order and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
The obtained crude crystals were purified by silica gel column chromatography to obtain 0.6 g (yield 59%) of a target product as a white powder.

[0068] Production Example 6 ^N 1 - [1- (2- benzoxazolyl) ethyl] -N ² - isopropoxycarbonyl -L- valinamide in the manufacture of dichloromethane 30ml (Compound 57) N-isopropoxycarbonyl -L 0.6 g of valine was dissolved, 0.3 g of N-methylpiperidine was added at -20 ° C, and the mixture was stirred at this temperature for 15 minutes. Next, 0.4 mL of isobutyl chloroformate was added to the mixture.
g was added at −30 ° C., and the mixture was stirred at −30 ° C. to −20 ° C. for 30 minutes. Add 1- (2-benzoxazolyl) to this reaction solution
After adding 0.5 g of ethylamine at −50 ° C., the mixture was stirred at room temperature for 15 hours except for the refrigerant. After completion of the reaction, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography, and 0.4 g of the desired product as a white powder was obtained.
(39% yield).

Production Example 7 Production of N ¹ -[(R) -1- (2-benzothiazolyl) ethyl] -N ² -isopropoxycarbonyl-L-valinamide (Compound No. 32) N-isopropoxycarbonyl- was added to 25 ml of dichloromethane. 1.5 g of L-valine was dissolved, 0.7 g of N-methylpiperidine was added at -20 ° C, and the mixture was stirred at this temperature for 10 minutes. Next, add 1.0 g of isobutyl chloroformate to the mixture.
g was added at −40 ° C., and the mixture was stirred at −40 ° C. to −15 ° C. for 1 hour. After 1.3 g of (R) -1- (2-benzothiazolyl) ethylamine was added to this reaction solution at -60 ° C, the mixture was stirred until the temperature reached room temperature except for the refrigerant. After completion of the reaction, the reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in this order,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography, and 0.5 g of the target substance as white powder (yield 1
9%).

[0070] Production Example 8 ^N 1 - [1- (5- Chloro-2
- benzothiazolyl) ethyl] -N ² - phenoxycarbonyl -L- valinamide (Compound No. 91) ^N 1 in the manufacture of dichloromethane 30ml of - [1- (5-Chloro -
2-benzothiazolyl) ethyl] -L-valinamide hydrochloride (0.4 g) was dissolved in N-methylpiperidine (0.24).
g was added at −50 ° C. and stirred at this temperature for 10 minutes. Next, 0.19 g of phenyl chloroformate was added to this mixture for -5 hours.
After the addition at 0 ° C., the mixture was stirred at room temperature for 15 hours except for the refrigerant.
After completion of the reaction, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography,
0.35 g (yield 70%) of the target product as a white powder was obtained.

[0071] Production Example 9 ^N 2-tert-butoxycarbonyl ^-N 1 - [1- (1- methyl-2-benzimidazolyl) ethyl] -L- valinamide (Compound No. 6
Preparation of 5) 0.41 g of N-tert-butoxycarbonyl-L-valine was dissolved in 40 ml of dichloromethane, and 0.19 g of N-methylpiperidine was added at -20 ° C.
Stirred for minutes. Next, 0.26 g of isobutyl chloroformate was added to this mixture at -40 ° C, and the mixture was stirred at -40 ° C to -15 ° C for 1 hour. 1- (1-Methyl-2-
0.33 g of benzimidazolyl) ethylamine in -60
After the addition at 0 ° C, the mixture was stirred until the temperature reached room temperature except for the refrigerant. After completion of the reaction, the reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in that order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography to obtain 0.53 g (yield 76%) of the target product as a white powder.

The fungicide for agricultural and horticultural use of the present invention has the general formula [I]
As an active ingredient. When the compound of the present invention is used as a fungicide for agricultural and horticultural use, it may be used as it is, but it is preferable to formulate and use the active ingredient in an appropriate dosage form according to the purpose. Normally, the active ingredient is diluted with an inert liquid or solid carrier, and if necessary, a surfactant, etc. may be added thereto, and the composition may be used in the form of powders, wettable powders, emulsions, granules, etc. .

The compounding ratio of the active ingredient is appropriately selected as required, but is 0.1 to 20% (by weight) in the case of powders and granules, and 5 to 80% (in the case of emulsions and wettable powders). Weight) is appropriate.

Examples of suitable carriers include solid carriers such as talc, bentonite, clay, kaolin, diatomaceous earth, white carbon, vermiculite, slaked lime, silica sand, ammonium sulfate, and urea; and liquid carriers such as isopropyl alcohol, xylene, cyclohexanone, and methylnaphthalene. Carriers and the like.

As the surfactant and the dispersant, for example,
Dinaphthylmethane disulfonate, alcohol sulfate, alkylaryl sulfonate, lignin sulfonate, polyoxyethylene glycol ether, polyoxyethylene alkylaryl ether, polyoxyethylene sorbitan monoalkylate and the like.

Examples of the auxiliary include carboxymethyl cellulose.

The agricultural and horticultural fungicides of the present invention prepared as described above are diluted to an appropriate concentration and sprayed or applied directly.

The application rate of the fungicide for agricultural and horticultural use of the present invention varies depending on the kind of the compound to be used, the target disease, the occurrence tendency, the degree of damage, the environmental conditions, the dosage form to be used, and the like. For example, when used as is, such as powders and granules,
The active ingredient may be appropriately selected from the range of 0.1 g to 5 kg, preferably 1 g to 1 kg per 10 ares. When used in liquid form such as emulsions and wettable powders, 0.1
ppm to 5,000 ppm, preferably 1 to 1,000 ppm
It is better to select from the range of ppm as appropriate.

The fungicide for agricultural and horticultural use of the present invention can be used for seed treatment, foliage application, soil application or surface application. As a result, plant diseases caused by bacteria belonging to algae (Oomycetes), ascomycetes (Ascomycetes), incomplete fungi (Deuteromycetes), basidiomycetes (Basidiomycetes), and other pathogenic bacteria can be controlled.

Next, specific bacterial names will be listed, but the present invention is not limited thereto. Phytophtho
ra) genus, for example, Phytophthora infestan
s), Plasmopara genus, for example, Plasmopara viticola, Pseudoperonospora, for example, Pseudoperonospora cubensis.

Further, the compound of the present invention may be mixed with other fungicides, insecticides, herbicides, plant growth regulators, fertilizers and the like, if necessary.

Next, the preparation method will be described in detail with reference to typical preparation examples of the agricultural and horticultural fungicides of the present invention. In the following description,% indicates weight percentage. Formulation Example 1 Dust 2% of the compound (1), 5% of diatomaceous earth and 93% of Cle-93 were uniformly mixed and pulverized to obtain a dust. Formulation Example 2 wettable powder 50% of compound (9), 45% of diatomaceous earth, 2% of sodium dinaphthylmethanedisulfonate and 3% of sodium ligninsulfonate were uniformly mixed and pulverized to obtain a wettable powder. Formulation Example 3 Emulsion 30% of compound (18), 20% of cyclohexanone, 11% of polyoxyethylene alkylaryl ether, 4% of calcium alkylbenzenesulfonate and 35% of methylnaphthalene were uniformly dissolved to form an emulsion. Formulation Example 4 Granules Compound (26) 5%, sodium salt of lauryl alcohol sulfate 2%, sodium lignin sulfonate 5
%, Carboxymethylcellulose 2% and clay 86%
Is uniformly mixed and pulverized. 20% of water was added to the mixture, and the mixture was kneaded, processed into granules of 14 to 32 mesh using an extrusion granulator, and then dried to obtain granules.

[0083]

The fungicide for agricultural and horticultural use of the present invention has an extremely high preventive effect against tomato blight, potato blight, grape downy mildew and cucumber downy mildew. Further, the agricultural and horticultural fungicide of the present invention exhibits an excellent therapeutically effective control effect by treating the pathogen after invading the plant.

On the other hand, the agricultural and horticultural fungicide of the present invention also has the characteristics that it does not cause harm to crops and is excellent in systemic transferability, residual effect, and rain resistance.

Next, the effects of the fungicide for agricultural and horticultural use of the present invention will be specifically described with reference to test examples. In addition, in the test,
The compounds described in EP 587110 were used as comparative agents.

[0086] Comparative agent ^A: N 2-tert-butoxycarbonyl ^-N 1 - [1- (1,3- dimethyl-2-indolyl) ethyl] -L- valinamide Comparative agent ^B: N 2-tert-butoxycarbonyl - N
¹ - [1- (3-methyl-2-indolyl) ethyl] -
L- valinamide Comparative agent C: ^{N 2} - benzyloxycarbonyl -N ¹ -
[1- (5-Chloro-1-methyl-2-indolyl) ethyl] -L-valinamide Comparative drug D: N ² -tert-butoxycarbonyl-N
¹ - [1- (5-chloro-3-methyl-2-benzo [b] thienyl) ethyl] -L- valinamide Comparative agent ^E: N 1 - [1- (2-benzo [b] thienyl) ethyl] - N ² -benzyloxycarbonyl-L-
Valinamide Comparative drug F: N ² -tert-butoxycarbonyl-N
¹ - [1- (3-chloro-2-benzofuranyl) ethyl] -L- valinamide Comparative agent ^G: N 1 - [1- (5-chloro-2-benzofuranyl) ethyl] -N ² - methoxycarbonyl -L- Valinamide

Test Example 1 Tomato Blight Prevention Effect Test One tomato seedling (variety: Ponterosa) was transplanted one by one into each of the unglazed pots having a diameter of 12 cm, and grown in a greenhouse. When the double leaves of the tomato seedling spread to 6 to 7 leaves, the wettable powder prepared according to Formulation Example 2 was diluted with water to 500 ppm with the active ingredient, and 20 ml per pot was sprayed. After the chemical solution attached to the tomato seedlings was dried, the tomato late blight (Phytop
hthora infestans) by spray inoculation,
It was left still in a humidity chamber at 2 ° C. Four days after the inoculation, the diseased area of each leaflet was examined.

The severity of the disease was evaluated according to the criteria shown in Table 7, and the degree of damage was determined from the severity and the number of leaves according to the following formula, and the control value was determined from the following formula. The results are shown in Table 8.

[0089]

[Table 7]

[0090]

(Equation 1)

[0091]

(Equation 2)

[0092]

[Table 8]

Test Example 2 Test for Preventive Effect of Grape Downy Mildew A grape seedling (cultivar: Kyoho) cut and grown in a clay pot having a diameter of 12 cm was pruned and grown in a greenhouse. When 4 to 5 leaves of the grape seedlings are developed, the wettable powder prepared according to Formulation Example 2 is diluted with water so that the active ingredient becomes 500 ppm,
20 ml was sprayed per pot. After drying the chemical solution attached to this grape seedling, the grape downy mildew (Plasmopara vit
icola) was spray-inoculated and allowed to stand in a humid chamber at 22 ° C. for 24 hours. Thereafter, the grape seedlings were transferred to a greenhouse to cause disease, and 7 days after inoculation, the grape seedlings were again placed in a humidity chamber at 22 ° C.
After allowing to stand for 4 hours, conidia were formed. The diseased area where conidiospores were formed in each leaf was investigated.

The severity of the disease was evaluated based on the criteria shown in Table 7, and the degree of damage was determined from the disease severity and the number of leaves in accordance with the above formula, and the control value was further determined from the formula. The results are shown in Table 9.

[0095]

[Table 9]

Test Example 3 Test for Preventive Effect of Cucumber Downy Milde Ten cucumber seeds (variety: Sagami Hanshiro) were sowed in each of 9 cm × 9 cm vinyl chloride pots, and grown in a greenhouse for 7 days. The wettable powder prepared according to Formulation Example 2 was diluted with the active ingredient to 500 ppm with water to the cucumber seedlings in which the cotyledons had developed, and 10 ml was sprayed per pot. After the medicinal solution attached to the cucumber seedlings was dried, a conidia suspension of cucumber downy mildew (Pseudoperonospora cubensis) was spray-inoculated and allowed to stand in a humidity chamber at 22 ° C. for 24 hours. Thereafter, the cucumber seedlings were transferred into a greenhouse, and 7 days after inoculation, the diseased area of the entire pot was examined.

Table 11 shows the results of evaluation based on the criteria in Table 10.
It was shown to.

[0098]

[Table 10]

[0099]

[Table 11]

Test Example 4 Test of therapeutic effect on cucumber downy mildew Ten cucumber seeds (variety: Sagami Hanshiro) were sowed in each of 9 cm × 9 cm polyvinyl chloride pots and grown in a greenhouse for 7 days. A conidia spore suspension of cucumber downy mildew (Pseudoperonospora cubensis) was spray-inoculated to the cucumber seedlings having cotyledons developed, and allowed to stand in a moist chamber at 22 ° C. for 24 hours. Thereafter, the cucumber seedlings were taken out of the humidity chamber at 22 ° C., and the water drops adhering to the cucumber seedlings were dried. 500 ppm of a wettable powder prepared according to Formulation Example 2 as an active ingredient
, And sprayed 10 ml per pot. After that, they were transferred into a greenhouse, and 7 days after the inoculation, the diseased area of the entire pot was examined.

Table 12 shows the results of evaluation based on the criteria shown in Table 10.
It was shown to.

[0102]

[Table 12]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07D 277/64 C07D 277/64 (72) Inventor Norihisa Yonekura 408-1, Shioda, Fukuda-cho, Iwata-gun, Shizuoka Prefecture Inside the Eye Research Institute (72) Inventor Jun-etsu Sakai 1809, Kamo, Kikugawa-cho, Ogasa-gun, Shizuoka Prefecture (72) Inventor Yoshiyuki Kojima 69, Takagosho, Kakegawa-shi, Shizuoka Prefecture (72) Inventor Shigeru Hayashi, 970 Shinno, Hamaoka-cho, Ogasa-gun, Shizuoka Prefecture No. 1 (56) References JP-A-5-140063 (JP, A) EP 602306 (EP, A1) Agric. Biol. Chem. , 41 (5), 811-18 (1977) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 235/14 C07D 263/56 C07D 277/64 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A compound of the general formula [In the formula, R ^1, Cl to 6 alkyl, C3-8 cycloalkyl group, a phenyl group (the phenyl group may be substituted one or more places in the same or different <br/> different halogen atoms ) Or a benzyl group; R ² represents a hydrogen atom or a methyl group; X represents a halogen atom, a methyl group, a methoxy group, a methylthio group, a cyano group or a trifluoromethyl group; 6 represents an alkyl group, A represents an oxygen atom, a sulfur atom or a group> NR ³ (R ³ represents a C1-6
A kill group, a C1-6 alkoxymethyl group or an acyl group . ) And n represents 0 or an integer of 1 to 3. ] The amino acid amide derivative represented by these. 2. The method according to claim 1, wherein A is a sulfur atom.
Amino acid amide derivatives. 3. The method according to claim 1, wherein R ¹ is a C1-6 alkyl group, R ² is a hydrogen atom or a methyl group, X is a halogen atom, a methyl group or a methoxy group, and Y is a C
1 to 6 alkyl groups, A is an oxygen atom, a sulfur atom or a group> NR ³ (R ³ represents an acyl group ), and n is 0
Or an amino acid amide derivative which is an integer of 1 to 3. 4. The method according to claim 1, wherein R ¹ is an isopropyl group, R ² is a methyl group, X is a fluorine atom, Y is an isopropyl group, A is a sulfur atom,
An amino acid amide derivative wherein n is 1. 5. The method according to claim 4, wherein X which is a fluorine atom is
Amino acid amide derivative linked to the 6-position. 6. A compound of the general formula [In the formula, R ^1, Cl to 6 alkyl, C3-8 cycloalkyl group, a phenyl group (the phenyl group may be substituted one or more places in the same or different <br/> different halogen atoms ) Or a benzyl group; R ² represents a hydrogen atom or a methyl group; X represents a halogen atom, a methyl group, a methoxy group, a methylthio group, a cyano group or a trifluoromethyl group; 6 represents an alkyl group, A represents an oxygen atom, a sulfur atom or a group> NR ³ (R ³ represents a C1-6
A kill group, a C1-6 alkoxymethyl group or an acyl group . ) And n represents 0 or an integer of 1 to 3. ] The fungicide for agricultural and horticultural use which contains the amino acid amide derivative represented by these as an active ingredient.