KR810001381B1 - Process for preparing novel isothiocyanate derivatives - Google Patents

Abstract

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Description

[Name of invention]

Process for preparing novel isothiocyanate derivatives

Detailed description of the invention

The present invention relates to a method for producing a novel isothiocyanate derivative. Some of the isothiocyanate derivatives are Belgian Patent No. 741.448, Canadian Patent No. 807,601, French Patent No. 1,545,679, German Patent No. 2,013,788, British Patent No. 1,183,113, Japanese Patent Publication No. 4523/1973, Japan Japanese Patent Publication Nos. 18,626 / 1975 and 1023/1977, Dutch Patent No. 67,12996, US Patent Nos. 3,530,161 and 3,887.358 and the like.

More specifically, the present invention relates to a compound having the following general formula and a salt thereof which are useful as agricultural fungicides.

Wherein X is oxygen or sulfur and R ¹ is hydroxy, C ₁ -C ₄ alkoxy, phenoxy, amino, C ₁ -C ₄ alkylamino, C ₂ -C ₈ dialkylamino, C ₆ -C ₁₀ aryl Amino, tetrahydrofurylamino, morpholino or methylpiperazino, but when X is sulfur R ¹ must be amino, C ₁ -C ₄ alkylamino, C ₂ -C ₈ dialkylamino or morpholino group, R ² is C ₁ -C ₄ alkoxy or C ₂ -C ₅ alkoxycarbonyl, R ³ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₈ dialkylamino or halogen .

As a further explanation to the above definition, the term “alkyl” is methyl, ethyl, propyl, isopropyl, butyl, isobutyl tert-butyl group or the like, and “alkoxy” is methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, tert-butoxy and the like, " alkylamino ＂" is methylamino, ethylamino, propylamino, isopropylamino, butylamino and the like, and dialkylamino is dimethylamino, methylethylamino, diethylamino, ethyl Butylamino, dibutylamino and the like, arylamino is phenylamino, tolyamino, xylylamino, mesitylamino, cumenylamino and the like, alkoxycarbonyl is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Isopropoxycarbonyl, butoxycarbonyl and the like, and halogen means fluorine, chlorine, cancellation, oxo and the like.

It is known that such isothiocyanate is useful as a germination regulator (Japanese Patent Laid-Open No. 1023/1977), and that isothiocyanate p-ethoxycarbonylphenyl is useful as an agricultural bactericide (Canada Patent No. 807,601). Reference). However, the bactericidal effect of this compound is insufficient for agricultural use.

The isothiocyanate phenyl derivative (I) of the present invention is synthesized as shown by the following scheme.

Wherein R ¹ , R ² and R ³ are each as defined above.

[Path I]

Isothiocyanate formation is performed by a well-known method. The raw material (II) is reacted with carbon disulfide and a base (e.g. triethylamine, pyridine, dimethylamine) in an organic solvent so that the intermediate produced is an alkyl halide carbonate (e.g. ethyl chlorocarbonate, chlorocarbonate in the presence or absence of an organic solvent). Methyl). Thus, phenyl isothiocyanate (Ia) was obtained.

Alternatively, phenyl isothiocyanate (Ia) is prepared by reacting raw material (II) with a halogenated dialkylthiocarbamoyl (eg, diethylthiocarbamoyl chloride) in an organic solvent.

Raw material (II) can be manufactured by a well-known method. For example, 3-diethylcarbamoyl-4-methoxy-5-methylaniline is prepared from 2-methoxy-3-methyl-5-nitrobenzoylchloride in two steps as follows.

[Path II]

The reaction for converting the carbamoyl group to the thiocarbamoyl group can be carried out by treating the raw material (II) with phosphorus pentasulfide in an organic solvent. Thus, thiocarbamoyl compound (III) was obtained.

[Path III]

The thiocarbamoyl compound (III) obtained above is used for the isothiocyanate formation reaction. This method can be carried out by the method described in Route I. Thiocarbamoylaniline (II) can be obtained by reducing the corresponding nitrobenzene derivative represented by the following structural formula.

Wherein R ¹ , R ² and R ³ are each as defined above. Thus, another product (Ib) was obtained.

[Path IV]

The first product (Ia) was reacted with thiocarbamoyl group formation. This route is carried out by treatment with phosphorus pentasulfide or dialkyl thiocarbamoyl / aluminum chloride in organic solvents, respectively. Thus, a second product Ib was also obtained.

[PATH V]

The second product (Ib) is prepared by treating raw material (II) directly with halogenated dialkylthiocarbamoyl / aluminum chloride in an organic solvent. Some of these reactions are carried out at temperatures between about 0-150 ° C., preferably between 45-100 ° C. Representative examples of the organic solvents include tetrahydrofuran, benzene, toluene, ethylene dichloride, methylene chloride and chlorobenzene.

Suitable and practical examples of the present invention are shown in the following examples.

Example 1

To a solution of methyl 2-methoxy-4-methyl-5-aminobenzoate (975 mg) in tetrahydrofuran (5 mL) was added triethylamine (1.52 g) and carbon disulfide (1.14 g), resulting in The mixture was stirred at rt for 2.5 h. Ethyl chlorocarbonate (1.63 g) was added to the mixture, which was further stirred at room temperature for 20 minutes. A solution of sodium hydroxide (1.2 g) in water (32 mL) was added to the mixture, which was stirred for 15 minutes. The reaction mixture was mixed with excess water and methylene chloride was added and shaken. The organic layer was dried over the glauber salt and the solvent was evaporated. The residue was dissolved in methylene chloride and chromatographed with silica gel column. The solvent was evaporated from the eluate, the residue was dissolved in isopropyl ether and n-hexane was added thereto. The precipitated crystals were filtered to give 3-methoxycarbonyl-4-methoxy-6-methylphenylisothiocyanate (952 mg) as crystals melting at 86-87.5 ° C.

Example 2-27

Using the following starting material (II), the reaction was carried out as in Example I to obtain the corresponding product (Ia).

Note: The abbreviations in the table have the following meanings.

H (hydrogen), Me (methyl group), Et (ethyl group), Pr (propyl group), Ph (phenyl group), DMA (dimethylamino group), DEA (diethylamino group), DEAEA (diethylaminoethylamino group), i ( Iso-), mp (melting point), IR (infrared spectrum).

Example 28

3- [N- (2,6-dimethylphenyl) carbamoyl] -4-methoxy-5-chloroaniline (650 mg), diethylthiocarbamoyl chloride (360 mg) and chlorobenzene (6 mL) The mixture with was refluxed for 30 minutes. The reaction mixture was mixed with water and shaken with the addition of methylene chloride. The organic worms were washed with water, dried over the glauber salt and concentrated to remove the solvent. The residue was chromatographed with a column of silica gel, which was eluted with methylene chloride. The eluted fractions were collected and the solvent was evaporated. The residue was recrystallized from ethyl acetate and melted at 191-192.5 ° C. as 3- [N- (2,6-dimethylphenyl) carbamoyl] -4-methoxy-5-chlorophenylisothiocyanate ( 340 mg) was obtained.

Example 29-33

Using the following starting material (II), the reaction was carried out as in Example 28 to obtain the following product (Ia).

Example 34

a) To a solution of 3-dimethylcarbamoyl-4-methoxy-5-methylnitrobenzene (1.10 g) in benzene (11 mL) is added phosphorus pentasulfide (3.08 g) and the resulting mixture is added for 1 hour. It was refluxed. After cooling, the reaction mixture was mixed with ice water and shaken with ether. The organic layer was washed with water, dried with a glauber salt and concentrated under reduced pressure to remove the solvent. The residue was chromatographed with a column of silica gel and eluted in the order of benzene, methylene chloride and methylene chloride 2% methanol. The eluted fractions were concentrated under reduced pressure and the residue was washed with isopropyl ether to melt at 138-139 ° C. as 3-dimethylthiocarbamoyl-4-methoxy-5-methyl-nitrobenzene (1.0 g). ) Was obtained.

b) Platinum dioxide hydrate (0.20 g) was added to a solution of the above product (0.95 g) in methanol (30 mL), and the resulting mixture was shaken in a hydrogen stream until the absorption of hydrogen ceased. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride, dried over the glauber salt and the solvent was evaporated. The residue was dissolved in dry tetrahydrofuran (5 mL) to prepare a solution, which was mixed with triethylaamine (1.13 g) and carbon disulfide (0.85 g), and the resulting mixture was stirred overnight at room temperature. Ethyl chlorocarbonate (1.22 g) was added to the mixture under cooling, which was stirred for 45 minutes under cooling. The mixture was treated with a 10% aqueous sodium hydroxide solution (9 ml), and methylene chloride was added thereto and shaken. The organic layer was washed with water, dried with glauber salt and the solvent was evaporated. The residue was chromatographed with a column of silica gel using methylene chloride as the eluent.

After evaporation of the solvent, the fraction produced brown oil (0.87 g), which was recrystallized from isopropylether petroleum ether and melted at 74-75 ° C. as 3-dimethylthiocarbamoyl-4-methoxy- 5-methylphenylisothiocyanate (312 mg) was obtained.

Example 35

To a solution of 3-dimethylcarbamoyl-4-methoxy-5-methylaniline (600 mg) in dry ethylene dichloride (12 mL) was added diethylthio carbamoyl chloride (850 mg) and the resulting mixture was Was refluxed for 25 minutes. Aluminum chloride (360 mg) was added to the mixture, which was refluxed for 2 hours. After cooling, the mixture was mixed with aqueous sodium bicarbonate solution, stirred at room temperature for 15 minutes, and shaken by addition of methylene chloride. The organic layer was washed with water, dried with a glauber salt and the solvent was evaporated under reduced pressure. The residue was chromatographed with a column of silica gel using methylene chloride as eluent.

The eluted fractions were evaporated and the residue was washed with isopropyl ether-petroleum ether and melted at 74-75 ° C. as 3-dimethylthiocarbamoyl-4-methoxy-5-methylphenyl-isothiocyanate (214 mg) was obtained.

Example 36

Reaction was carried out as in Example 35 using 3-diethylcarbamoyl-4-methoxyphenylisothiocyanate (700 mg) to give 3-diethylthio as a colorless needle that melted at 121-122 占 폚. Carbamoyl-4-methoxyphenylisothiocyanate (437 mg) was obtained.

Example 37-39

The same reaction as described in Example 34a) was carried out to obtain the following compound.

Phenylisothiocyanate (I) is useful as an agricultural fungicide for various plant pathogens, such as cucumber powdery mildew disease, cucumber disease, cucumber anthrax disease, rice killing disease, and dead kill disease of various crops. The excellent control effect of compound (I) is demonstrated in the following Example. The compound described next is the test compound used for the experiment.

Experimental Example 1

[Control Effect Test on Oythrax Anthrax]

Seeds of cucumbers (varieties, Matsuzawa) were filled with a 9 cm diameter vinyl chloride cup, and sown one seed per cup and placed in a greenhouse. When the first leaf appeared, 5 ml of the test compound solution was used in the cup at the concentration described above. After use, the cup was kept at a temperature of 25-26 ° C. and 80% humidity for 1 day. Spore suspensions of the colletotrichum lagenarium were inoculated at five points per leaf on the first leaf of cucumber described above.

The cup was kept at a temperature of 25 ° C. and a humidity of 95% for 1 day. After six days at 25 ° C. and 75-80% humidity, the degree of disease in the inoculated portion was observed. The percentage of disease control was calculated using the following equation.

The results are shown in Table 1.

TABLE 1

Experimental Example 2

[Control effect test for Oinobacteria disease]

Cucumber seeds were filled with soil in a cup of 9 cm diameter vinyl chloride, and one seed was sown in each cup and placed in a silver chamber. When the first leaf appeared, 5 ml of the test compound solution was used in the cup at the concentrations described above. After use, the cup was kept at a temperature of 20-22 ° C. for 1 day. Spore suspension of cucumber Pseudoperonospora cubensis was sown at five points per leaf on the first leaf of cucumber described above. The cup was held at a temperature of 20 ° C. and a humidity of 95% for 10 days. The degree of disease in the inoculated portion was observed. Percent disease control was calculated using the following equation.

The results are shown in Table 2.

TABLE 2

Experimental Example 3

[Test of Control Effect on Cucumber Powdery Mildew Disease]

Seeds of cucumber (varieties, Matsuzawa) were filled with soil in a cup of 9 cm diameter vinyl chloride, and one seed was sown in each cup and placed in a greenhouse. When the first leaf appeared, 5 ml of the test compound solution was used in the cup at the concentrations described above. After use, the cup was kept at a temperature of 25-26 ° C. for 1 day. Cucumbers infected by the plant pathogen of Sphaero theca fuliginea were taken and cut into 1 square centimeter pieces of cucumber-covered pests. The pathogens were covered with odia and inoculated on the first leaves of potted cucumbers with 4 parts per leaf. This cup was then held at a temperature of 25-26 ° C. for 10 days. Odium formation was observed under the microscope inoculated leaves.

+: Infected spots and Odiadia formation were observed at the inoculation site.

-: No spots and no formation of Odium were observed.

The results are shown in Table 3.

TABLE 3

Experimental Example 4

[Control Effect Test on Rice Death Disease]

Rice seedlings (cultivar, Aichi-Asahi seedlings) grown in a greenhouse for 10 days were transplanted into a 12 cm diameter vinyl chloride cup filled with soil. A solution of the test compound was used about 14 days after transplanting at the aforementioned concentration. After one day, a spore suspension of a plant pathogen of Pyricularia oryzae was sprayed on the seedling leaves, and the cup was kept at a temperature of 28 ° C. and a humidity of 68% for 24 hours. It was kept in the greenhouse for 7 days at a humidity of 90% The number of spots on the inoculated leaves was observed and the percentage of disease control was calculated using the following equation.

The results are shown in Table 4.

TABLE 4

Experimental Example 5

[Test for Controlling Effect of Cucumber Seedlings on Mycelial Disease]

150 ml of sterile soil was placed in a pot of 9 cm in diameter, and 20 cucumber seeds were planted per pollen. Pathogens of Pythium aphanidermatum, Fusarium, oxysoirum.Rhizoctonia solani were incubated in bran medium for 5 days, then mixed with sterile soil and incubated at 25 ° C. for 2 days. 30 ml of test compound was sprayed into each pot at the concentrations described above, and the pot was kept in a greenhouse for 11 days at a temperature of 28 ° C. Disease levels were observed in the treated pollen. The degree of disease and the percentage of disease prevention were calculated using the following equation.

The results are shown in Table 5.

Thus, phenyl (I) isothiocyanate showed a strong bactericidal effect against Oythrax aneurysm, Oinobacterial disease, Cucumber powdery mildew, Rice blast disease and Oyomophyte spp. Other compounds of formula (I) showed a bactericidal effect similar to that of the former.

The product (I) of the present invention can be used in a form suitable for agricultural fungicides such as emulsions, solutions, hydrates, powders, suspensions, granules, aerosols, emulsions, mists and pastes. Compound (I) can be used alone or in combination with a solid or liquid carrier. Examples of solid carriers include clay, talc, diatomaceous earth, silica, kaolin, bentonite, pumice, and the like. Examples of liquid carriers include water, methanol, ethanol, ethylene glycol, dimethylformamide, dimethyl sulfoxide, acetone, and methyl ethyl ketone. , Cellosolve, dioxane, diglyme, and the like can be used. If necessary, suitable auxiliaries such as emulsifiers, dispersants, dusting agents, surfactants, hydrating agents, stabilizers, synergists and the like can be added. In addition, the compound (I) can be used in combination with other pesticides, such as other fungicides, fungicides, insecticides, herbicides, insect repellents, tick devices, nematicides, plant growth regulators. The amount of the liquid agent of compound (I) is about 50-2,000 ppm per 10 ars, suitably 100-1,000 ppm and 100-200 L, and the amount of solids is about 3-4 kg per 10 arees.

Fungicides containing compound (I) are described in the following formulation examples.

[Example 1]

50 parts by weight of 3-methoxycarbonyl-4-methoxyphenylisothiocyanate, 35 parts by weight of diatomaceous earth, 10 parts by weight of white carbon, 2 parts by weight of sodium alkylbenzenesulfonate and 3 parts by weight of calcium lignin sulfonate The hydrate was prepared by mixing.

[Example 2]

30 parts by weight of 3-methoxycarbonyl-4,6-dimethoxyphenylisothiocyanate, 40 parts by weight of xylene, and cyclohexa 20 parts by weight and 10 parts by weight of polyoxyethylene alkyl ether are mixed and stirred to prepare an emulsifier. did.

[Example 3]

3 parts by weight of 3-methoxycarbonyl-4,5-dimethoxyphenylisothiocyanate, 7 parts by weight of talc and 90 parts by weight of clay were mixed and ground to prepare a powder.

[Example 4]

3 parts by weight of 3-methoxycarbonyl-4,6-dimethoxyphenylisothiocyanate, 2 parts by weight of sodium alkylbenzenesulfonate, 45 parts by weight of clay and 50 parts by weight of bentonite, are mixed with a suitable amount of water, kneaded and granulated Assembled. Air granules were dried at 50 ° C. and sieved to 20-40 mesh screens to prepare the desired granules. Such granules are used directly.

Phenyl isothiocyanate (I) is also useful as an antifungal agent in humans and animals. For example, 3-methoxycarbonyl-4,5-dimethoxyphenylisothiocyanate exhibited a minimum inhibitory concentration of 6.2γ / ml against Candida albicans M-9 in an in vitro test.

Claims (1)

A process for producing a novel isothiocyanate phenyl derivative of the general formula (I) by reacting a compound produced by reacting a compound of the general formula (II) with carbon disulfide and a base.

Wherein x is oxygen or sulfur and R ¹ is hydroxy, C ₁ -C ₄ alkoxy, phenoxy, amino, C ₁ -C ₄ alkylamino, C ₂ -C ₈ dialkylamino, C ₆ -C ₁₀ Arylamino, tetrahydrofurfurylamino, morpholino or methylpiperazino groups and when x is sulfur R ¹ must be amino, C ₁ -C ₄ alkylamino, C ₂ -C ₈ dialkylamino or morpholino group R ₂ is C ₁ -C ₄ alkoxy or C ₂ -C ₅ alkoxycarbonyl, R ³ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₈ dialkylamino Or halogen.