JPH044310B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [ ^{In the formula ,} Each represents an amino group.) An ethyleneimino group, a morpholino group, or a 2,6-dimethyl-4-morpholino group. The present invention relates to 5-methylthiopyrimidine derivatives represented by the following formulas, methods for producing the same, and agricultural and horticultural fungicides containing these compounds as active ingredients. A large number of studies have been conducted on pyrimidine derivatives, a huge number of compounds have been synthesized, and many compounds have been discovered that exhibit characteristic physiological activities in the field of agricultural medicine. However, in many cases, substituents at the 2, 4, and 6 positions of the pyrimidine skeleton, which are easy to manufacture, are exchanged, and the 5-position has low reactivity, so direct introduction of substituents requires nitration, halogenation, etc. There are only a few known methods for performing this under limited conditions. Among the substituents at the 5-position, there are few synthesis examples of compounds having a methylthio group and an amino group at the 2-, 4-, or 6-position of the pyrimidine skeleton. The only related compounds listed in Chemical Abstracts are listed below.

【table】

[Table] The present inventors focused on the fact that no compound having a methylthio group at the 5th position, a methoxy group at the 2nd and 4th positions, and an amino group at the 6th position has been synthesized to date. As a result of synthesizing various derivatives and testing their physiological activities, we found that these compounds of the present invention have extremely excellent control effects against many plant pathogens, which could not be expected from known compounds. The present invention has been completed. The compounds of the present invention have excellent bactericidal and growth-inhibiting properties against plant pathogens, and can be applied to control plant diseases caused by a wide variety of fungi.
For example, the compound of the present invention can be used as a spray agent or soil treatment agent to treat potato late blight, tomato late blight, green pepper late blight, yellowtail mildew, etc. caused by algal fungi, or botrytis blight, apple spot leaf blight caused by Deuteromycetes, and the like.
It is highly effective against powdery mildew of various crops caused by ascomycetes. Furthermore, the compounds of the present invention do not show any practical damage to cultivated plants. warm-blooded animals, such as mice,
It has extremely low toxicity to rats, dogs, chickens, etc., and shows no toxicity to fish, and has extremely excellent properties as an agricultural fungicide. The compound of the present invention can be produced according to route (a) or (b) of the following reaction formula. (X in general formulas () to () is the same as above) Starting material 5-methylthio-2,4,6-
Trichloropyrimidine can be produced according to the method described in Chemical Abstracts 72, 3499s. Below, the manufacturing method of the present invention will be explained in detail for each step based on the above reaction formula. Route (a) Step (i): Tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide,
Something inert to the sodium metal, such as benzene, toluene or ether, or methanol itself can be used. For the reaction, first dilute 2 equivalents or a slight excess of methanol into the solvent (if methanol is used as the solvent, use the required volume),
Add an equivalent amount or a slight excess of sodium metal or sodium hydride and stir well to adjust the sodium methylate. After the sodium methylate is formed, 5-methylthio-2,4,6-trichloropyrimidine is added in portions, either as a solid or dissolved in a solvent. In this case, the reaction temperature is −10
℃ to the boiling point of the solvent, but when added below room temperature, 6-chloro-2,4-dimethoxy-5-methylthiopyrimidine is produced with good selectivity. The product can be easily isolated, but it can also be carried on to the next step (ii) without isolation. Step (ii): As the solvent, the same solvent as in step (i) can be used, and water can also be used for amines with a low boiling point. As a deoxidizing agent, tertiary amines such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, triethylamine, etc. or those represented by the general formula ()
XH itself can be used. In the presence of the above deoxidizing agent, 6-chloro-2,4-dimethoxy-5
-XH() in a solution of methylthiopyrimidine
Add 1 equivalent or a slight excess of. The reaction temperature can range from 0°C to the boiling point of the solvent, but when heated,
In many cases, the reaction is completed in 2 to 4 hours. In the case of amines with a low boiling point, an autoclave may be used. The produced target compound represented by the general formula () is purified by recrystallization or column chromatography. Route (b) Step (iii): Same as step (ii). In the presence of a deoxidizing agent, 1 equivalent or a slight excess of XH represented by the general formula () is added to a solution of 5-methylthio-2,4,6-trichloropyrimidine. Reaction temperature is 0℃
to the boiling point of the solvent, but side reactions such as polysubstituted products can be prevented by performing the reaction at temperatures as low as room temperature or below. The reaction is often completed in 2 to 5 hours. The compound represented by the general formula () can be easily isolated by recrystallization or column chromatography, but it can also be directly carried on to the next step (iv) without being isolated. Step (iv): Same as step (ii). In a solution of 2 equivalents or a slight excess of sodium methylate, the general formula ()
or a previously prepared solution of sodium methylate may be added to the solution of the compound of general formula (). The reaction temperature can range from room temperature to the boiling point of the solvent, but heating progresses more smoothly, and the reaction is often completed in 2 to 5 hours. The method for purifying the target compound is the same as in step (ii). The method for producing the compound of the present invention will be specifically explained below by giving synthesis examples. Synthesis example 1 2,4-dimethoxy-6-(N-methylamino)
-5-methylthiopyrimidine (compound number 1)
Synthesis...route (a) Synthesis of 6-chloro-2,4-dimethoxy-5-methylthiopyrimidine Add 30 ml of anhydrous methanol to a 50 ml four-necked flask equipped with a reflux condenser with a calcium chloride tube, a thermometer, and a stirrer. After charging, 0.37 g of sodium metal was added in small pieces. After the metallic sodium was dissolved, 1.84 g of 5-methylthio-2,4,6-trichloropyrimidine was added little by little at 0°C. at 0℃
After stirring for 15 minutes at room temperature, the reaction solution was poured into ice water. The precipitated solid was collected and recrystallized from isopropyl alcohol to give 6-chloro-2,4-dimethoxy-5-methylthiopyrimidine (mp58.5
~59.5°C) was obtained. Yield 1.40g (yield 79.1%)
NMR (CCl ₄ ) δ2.30 (3H, s,), 3.97 (3H, s)
4.04 (3H, s) The singlet peaks that appear at NMR δ values of 3.97 and 4.04 each correspond to three hydrogen atoms,
Due to two methoxy groups. Moreover, since the singlet peaks are unequal, the obtained compound is 6-chloro-2,4-dimethoxy-5
-Identified as methylthiopyrimidine. Synthesis of 2,4-dimethoxy-6-(N-methylamino)-5-methylthiopyrimidine In an autoclave, 1.76 g of 6-chloro-2,4-dimethoxy-5-methylthiopyrimidine and 40
% methylamine aqueous solution and 25 ml of dimethyl sulfoxide were heated at 110° C. for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. After washing and dehydrating,
The crude product obtained by removing the solvent was recrystallized from isopropyl ether to give 2,4-dimethoxy-6-
(N-methylamino)-5-methylthiopyrimidine (mp 57.5-59°C) was obtained. Yield 1.37g (yield 80
%). NMR (CCl ₄ ) δ2.08 (3H, s), 4.99 (3H, d,
J=4.8Hz), 3.86 (3H, s), 3.92 (3H, s), 5.94
(1H, broad) Synthesis example 2 2,4-dimethoxy-5-methylthio-6-
Synthesis of (N-phenylamino)pyrimidine (compound number 2)...Route (b) 2,4-dichloro-5-methylthio-6-
Synthesis of (N-phenylamino)pyrimidine
5-methylthio-2,4,6 in a 4-necked flask
- 2.30 g of trichloropyrimidine, potassium carbonate
2.76 g and 30 ml of dimethyl sulfoxide were charged and suspended. 1.12 g of aniline was added and stirred at room temperature for 3 hours. The reaction solution was poured into dilute hydrochloric acid and extracted with ethyl acetate. After washing with water and dehydration, the crude product obtained by removing the solvent was recrystallized from isopropyl ether and 2,4-dichloro-5-methylthio-6-(N
-phenylamino)pyrimidine (mp130~131℃)
I got it. Yield: 1.63g (yield 57%). NMR (CDCl ₃ ) δ2.39 (3H, s), 7.1−7.7 (5H,
m), 8.44 (1H, broad) 2,4-dimethoxy-5-methylthio-6-
Synthesis of (N-phenylamino)pyrimidine A 100 ml four-necked flask equipped with a reflux condenser with a calcium chloride tube, a thermometer and a stirrer was charged with 30 ml of anhydrous methanol. Next, metallic sodium 0.55
Add 2,4 g in small pieces and after completely dissolving
1.14 g of -dichloro-5-methylthio-6-(N-phenylamino)pyrimidine was added at room temperature. 2
After heating under reflux for an hour, the reaction solution was poured into dilute hydrochloric acid and extracted with ethyl acetate. After washing with water and dehydration, the crude product obtained by removing the solvent was recrystallized from n-hexane and 2,4-dimethoxy-5-methylthio-6-(N
-phenylamino)pyrimidine (mp -65~68℃)
I got it. Yield: 0.73g (66% yield). NMR (CCl ₄ ) δ2.20 (3H, s), 3.92 (3H, s),
3.99 (3H, s), 6.99 (1H, d, J=8.0Hz), 7.24
(2H, dd, J=8.0, 8.0Hz), 7.62 (2H, d, J=
8.0Hz), 8.08 (1H, broad) The singlet peaks that appear at NMR δ values of 3.92 and 3.97 correspond to three hydrogen atoms, respectively.
Due to two methoxy groups. Moreover, since these singlet peaks are unequal, the obtained compound, 2,4-dimethoxy-5-methylthio-
6-(N-phenylamino)pyrimidine was identified. Any of the compounds of the present invention represented by the general formula () can be synthesized according to the above synthesis examples. The compounds of the present invention produced by the above method and their physical properties are shown in Table 1 below.

【table】

[Table] The compound of the present invention can be used as it is as an agricultural and horticultural fungicide, but in reality, it is mixed with a carrier and other auxiliary agents as necessary to form a formulation commonly used as an agricultural and horticultural fungicide, such as a powder. , coarse powder,
It is prepared and used as fine granules, granules, wettable powders, emulsions, aqueous solutions, aqueous solutions, oil suspensions, etc. The carrier here refers to a synthetic or natural carrier that is added to agricultural and horticultural fungicides to help the active ingredient reach the area to be treated and to facilitate the storage, transportation, and handling of the active ingredient compound. means an inorganic or organic substance. Suitable solid carriers include clays such as montmorillonite and kaolinite, inorganic materials such as diatomaceous earth, clay, talc, vermiculite, gypsum, calcium carbonate, silica gel, and ammonium sulfate, and vegetable organic materials such as soybean flour, sawdust, and wheat flour. substances, urea, etc. Suitable liquid carriers include benzene, toluene,
Aromatic hydrocarbons such as xylene and cumene, paraffinic hydrocarbons such as kerosene and mineral oil, halogenated hydrocarbons such as carbon tetrachloride, chloroform and dichloroethane, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane and tetrahydrofuran. , alcohols such as methanol, propanol, and ethylene glycol, dimethylformamide, dimethyl sulfoxide, and water. Furthermore, in order to enhance the efficacy of the compound of the present invention, the following adjuvants may be used alone or in combination depending on the purpose, taking into consideration the dosage form of the preparation, the application situation, etc. For purposes of emulsification, dispersion, spreading, wetting, binding, stabilization, etc., water-soluble bases such as lignin sulfonates, anionic surfactants such as alkylbenzene sulfonates and alkyl sulfate esters, and non-containing surfactants such as polyoxyethylene allyl ether are used. Ionic surfactants, calcium stearate, lubricants such as wax, stabilizers such as isopropylhydrodiene phosphate,
Other examples include methylcellulose, carboxymethylcellulose, casein, and gum arabic. However, these components are not limited to the above. Also, when the compound of the present invention is applied as a fungicide, other agricultural chemicals, such as insecticides,
Fungicides, acaricides, nematicides, antiviral agents, herbicides, plant growth regulators, attractants, such as organic phosphate compounds, carbamate compounds, dithiocarbamate compounds, thiol carbamate compounds, organic It can also be used in combination with chlorine compounds, dinitro compounds, antibiotics, urea compounds, triazine compounds, fertilizers, etc., or as a mixture. The various formulations or spray preparations containing the active ingredients of the present invention can be applied by application methods customary in the field of agrochemical manufacturing, namely spraying, spraying, misting, atomizing, dusting, granulating, etc. , water surface application), fumigation, soil application (e.g. incorporation, fumigation, irrigation), surface application (e.g. spreading, dusting, covering), immersion, etc. Next, the formulation method of the agricultural and horticultural fungicide of the present invention will be explained with reference to Examples. The active ingredient compounds are shown in the synthesis examples and compound numbers in Table 1 above. "Part" represents "part by weight." Example 1 Wettable powder Compound 3: 300 parts, diatomaceous earth: 440 parts, white clay:
200 parts, sodium ligninsulfonate: 25 parts,
Sodium alkylbenzenesulfonate: 15 parts,
and polyoxyethylene nonyl phenyl ether: 20 parts were uniformly ground and mixed to obtain a wettable powder containing 30% of Compound 3 as an active ingredient. Example 2 Emulsion Compound 15: 400 parts, cyclohexanone: 100 parts,
300 parts of xylene and 200 parts of Solpol (a surfactant manufactured by Toho Chemical) were uniformly dissolved and mixed to obtain an emulsion containing 40% of Compound 15 as an active ingredient. Example 3 Granule Compound 2: 10 parts, bentonite: 62 parts, talc: 20 parts, sodium dodecylbenzenesulfonate: 2 parts, and sodium ligninsulfonate: 1 part were mixed, and an appropriate amount of water was added and kneaded. Thereafter, the mixture was granulated in a conventional manner using an extrusion granulator to obtain granules containing 10% of Compound 2 as an active ingredient. Example 4 Powder Compound 8: 20 parts, calcium stearate: 5
part, powdered silica gel: 5 parts, diatomaceous earth: 200 parts,
300 parts of white clay and 470 parts of talc were uniformly ground and mixed to obtain a powder containing 2% of Compound 8 as an active ingredient. Example 5 Oil Compound 17: 10 parts and ethyl cellosolve: 90
Mix and dissolve 10 parts of Compound 17 as the active ingredient.
An oil solution containing % was obtained. Next, the effect of the compound of the present invention as a fungicide will be explained in detail using test examples. The test compounds are shown by the compound numbers in the Synthesis Example and Table 1 above. Test Example 1 Apple Spot Leaf Disease Test Apple seedlings (variety: Starking, 2-year-old seedlings) with approximately 8 newly developed leaves planted in a No. 3 clay pot were treated with a prescribed concentration of the drug (test compound of Example 1). Using a spray gun (1.0Kg/cm ² ), use
100ml was sprayed per pot. After air-drying, a conidial suspension of a pre-cultured apple spot defoliation fungus (cultivated for 7 days in V-8 vegetable juice medium) was spray inoculated and maintained at a temperature of 23 to 25°C and a humidity of 95% or higher for 3 days. The number of lesions was investigated on each of the 8 leaves in each pot, and 1
The average number of lesions per leaf was determined, and the control value was calculated using the following formula. Control value (%) = (1 - average number of lesions in sprayed area/average number of lesions in non-sprayed area) x 100 The results are shown in Table 2 below.

【table】

[Table] Test Example 2 Botrytis blight control test Expanded green bean cotyledons (variety: Topcrop) were mixed with a chemical solution of a specified concentration (the test compound was made into a wettable powder by the method of Example 1 above, and this was mixed with water to the specified concentration). (diluted to a certain concentration) for 1 minute. After air drying,
Pre-cultured gray mold fungus (Botrytis)
cinenea (cultivated for 5 days in PSA medium) mycelial pieces (diameter 6 mm) were placed on kidney bean leaves and incubated at a temperature of 20°C.
The humidity was maintained at over 95% for 4 days. The diameter of the lesion on each leaf was investigated, and the control value was calculated using the following formula. Control value (%) = (1 - average lesion diameter of treated area/average lesion diameter of untreated area) x 100 The results are shown in Table 3 below.

[Table] Test example 4 Potato late blight control test Potatoes grown in pots in a greenhouse (varieties,
A predetermined concentration of the drug (the test compound was made into a hydrating agent using the method of Example 1 and diluted with water to a predetermined concentration) was applied to a 3-year-old man's peacock, plant height approximately 25 cm, using a spray gun. Spread 50ml per pot and air dry. A zoospore suspension was prepared from Phytophthora bacillus which had been cultured in advance on potato sections for 7 days,
This suspension was further maintained at 7°C for 3 hours to prepare a zoospore suspension. This suspension was spray-inoculated onto the drug-sprayed potato plants, and the test plants were grown at a temperature of 17 to
After being kept at 19°C and humidity of 95% or higher for 5 hours, the degree of lesion formation was investigated. The evaluation criteria are as follows. Disease severity 0: Lesion area ratio 0% 1: 1-5% 2: 6-25% 3: 26-50% 4: 51% or more The results are shown in Table 4.

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Claims (1)

[Claims] 1 General formula () [ ^{In the formula ,} each represents an amino group), an ethyleneimino group, a morpholino group, or a 2,6-dimethyl-4-morpholino group. ] A 5-methylthiopyrimidine derivative represented by: 2 5-Methylthio-2,4,6-trichloropyrimidine and sodium methylate are reacted to produce 6-chloro-2,4-dimethoxy-5-methylthiopyrimidine, which is then expressed by the general formula
XH [wherein, X is -NR ¹ R ² (R ¹ and R ² are hydrogen atoms,
Each represents an alkyl group, alkenyl group, phenyl group, alkoxycarbonylalkyl group, carboxyalkyl group, aminoalkyl group, or amino group having 1 to 3 carbon atoms. ), ethyleneimino group,
Represents a morpholino group or a 2,6-dimethyl-4-morpholino group. ] General formula () characterized by reacting with amines represented by A method for producing a 5-methylthiopyrimidine derivative represented by the formula (wherein, X is the same as above). 3 5-methylthio-2,4,6-trichloropyrimidine and general formula XH [wherein, X is -NR ¹ R ² (R ¹ ,
^R2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkenyl group, a phenyl group, an alkoxycarbonylalkyl group, a carboxyalkyl group, an aminoalkyl group, or an amino group, respectively. ), ethyleneimino group, morpholino group, or 2,6-
Represents dimethyl-4-morpholino group. ] by reacting with amines represented by the general formula () (In the formula, X is the same as above.) A general formula () characterized by producing a compound represented by the formula (wherein, X is the same as above) and then reacting this with sodium methylate. (In the formula, X is the same as above.) A method for producing a 5-methylthiopyrimidine derivative. 4 General formula () [ ^{In the formula ,} each represents an amino group), an ethyleneimino group, a morpholino group, or a 2,6-dimethyl-4-morpholino group. ] An agricultural and horticultural fungicide characterized by containing a 5-methylthiopyrimidine derivative represented by the following as an active ingredient.