JPS6183174A - 5-nitro-4-trifluoromethylthiazole derivative, its preparation, and fungicide - Google Patents

Abstract

NEW MATERIAL:5-Nitro-4-trifluoromethylthiazole derivative of formula I (X is halogen, lower alkyl, trifluoromethyl or trifluoromethoxy; m is 0 or 1-2; n is 0 or 2). EXAMPLE:2-(Phenylthio)-5-nitro-4-(trifluoromethyl)thiazole. USE:A fubngicide. Useful especially as an agent effective to the pathogen of human body such as candidasis, trichomoniasis, and athlete's foot, and to the blight of agricultural and horticultural plants. PREPARATION:The objective compound of formula I can be prepared by reacting 5-nitro-4-trifluoromethyl-2-halogenothiazole of formula II (Y is halogen) with the compound of formula III (Z is SH or SO2Na). The starting compound of formula II is also novel, and can be synthesized e.g. by reacting 2-amino-5- nitro-4-trifluoromethylthiazole with a halogenation agent.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to novel 5-nitro-4-trifluoromethylthiazole derivatives, production methods, and fungicides containing the compounds as active ingredients, particularly for treating candidiasis, It is a fungicide that is effective against human pathogens such as trichomoniasis and athlete's foot, and against agricultural and horticultural plant diseases.

(Prior Art) It is known that 5-nitrothiazole derivatives shown below exhibit bactericidal activity.

b) Patent No. 11838-22885 FL: H, CH,, Indicates a hydrogen atom, .01-4)-loweryl, haloalkenyl. ) C) German Patent No. 2,627,328 (R represents a hydrogen atom or 01~.alkyl, C8~.alkyl, cyclopentyl or cyclohexyl) =) J, Prakt, Chem 1974 316
(2) P349-52 (n' is O or 2, chicken is methyl,
Chlor, nitro, t-butyl, Go represents 1 or 2.

) (Problems to be Solved by the Present Invention) The above-mentioned known 5-nitrothiazoles have bactericidal activity against bacteria (2), but show only weak activity against human pathogens such as Candida, Trichomonas, and athlete's foot. It has skin irritation properties and is difficult to use in practice as an antifungal agent.

The purpose of the present invention is to find useful compounds with excellent antifungal activity.

In the agricultural field, many pesticides are used to control crop diseases during crop cultivation, but their use is limited due to insufficient control efficacy or the emergence of drug-resistant bacteria. In addition, many fungicides cannot be said to be satisfactory because they cause phytotoxicity or contamination of plants, or are highly toxic to humans, animals, fish, and shellfish.

Another object of the present invention is to find a drug that has fewer of the above-mentioned drawbacks and can be used safely.

(Means for solving the problem - Compounds and manufacturing methods) Fluorine atoms are the smallest atoms in the halogen group, and are easily incorporated into living organisms due to the mimic (m1m1c) effect. Their fat solubility tends to increase, making them easier to absorb and transport within the body, thereby enhancing their effectiveness as drugs.

The present inventors focused on the introduction of a trifluoromethyl group and focused on the general formula (wherein,
1 or 2, and n represents 0 or 2. ) was manufactured and tested and found to have excellent bactericidal efficacy against not only bacteria but also plant pathogens and human pathogens such as Cancita, Trichophyton, and Trichomonas, and also has antitumor activity.

The compound of the present invention is represented by the general formula (wherein, Y represents a halogen atom).
Nitro-4-trifluoromethi)v-2-halogenothiazole and a compound represented by the general formula (wherein 2 represents SH or 50.Na, and X and m have the same meanings as above). It can be produced by reaction in an organic solvent.

When 2 is an SH group, it is preferable to add an acid binder. As the acid binder, alcoholado, sodium chloride, potassium hydroxide, soda carbonate, etc. can be used.

As the organic solvent, polar solvents such as ethanol and methanol can be used.

Further, the sulfone derivative (n=2) of the compound of the present invention can be produced by oxidizing the compound represented by the general formula obtained as described above using an oxidizing agent. As the oxidizing agent, methachlorobenzoic acid, a hydrogen peroxide aqueous solution, etc. can be used.

5-etho-4- which is a raw material compound for the production method of the present invention
Trifluoromethyl-2-halogenothiazoles are new compounds, such as 2-amino-5-nitro-4-t!
It can be produced by reacting j-fluoromethyl'j-7sol with a halogen atom.

(Example - Compound/Production method) Next, the production method of the present invention will be further explained in detail with reference to Examples.

Example 1. Compound 1° metallic sodium 0.13 F (5,5 mriatom) was dissolved in absolute ethanol 20°. This solution was kept at 0°C, and while stirring, 0.59 N (thiophenol) (0.59 N (5° 4 mmol))
was added, and then 2-bromo-5-nide a-4- was added at the same temperature.
(1'lifluoromethyl)thiazo-A/1. s i (
5.4 mmol N) was added. 5℃ after fever disappeared
The mixture was stirred for 1 hour.

The reaction mixture was vacuumed to remove ethanol, and the residue was extracted by adding chloroform 31)+4 and water 2o-. The chloroform layer was separated, washed with water 2ojlj, and then dried over anhydrous magnesium sulfate. Under reduced pressure (double concentration to dryness and 2-(
A crude product 1.4Ii of phenylthio)-5-nitro-4-(trifN-olmethyl)thiazole was obtained.

This was recrystallized from ethanol to obtain a purified product of 0.901. Melting point 12L5-123.5℃, mass spectrum m
/ej: 306 M” Example 2. Compound 2゜2-(phenylthio)-5-nitro-4-(trifluoromethyN)thiazole 400! (1.3 mmol)
Dissolve it in chloroform and make methachlorobenzoin! 0
．． 7 J' was added and oxidized under reflux for 3 hours. After the reaction mixture was cooled and the product was separated, the r solution was dried under reduced pressure.

The residue was subjected to two-layer chromatography (column: silica gel, developing solvent: benzene + n-hexene (1:1).
1)) to produce 2-(benzenesulfony)-5-
Nitro-4-(1,1 fluoromethyl 1L/)thia/-
Yellow crystals of 120F were obtained.

Melting point 126-127℃, wxx Pect A/M/e/;3
38 M" Example 3 Ethanol 20+11/(nee 2-plum-5-nitro-4-(trifluoromethyl)thiazo-Al1.77
N (10 mmol) was added and dissolved, and 1.64 N (10 mmol/I/l) of sodium benzenesulfonate was added thereto under stirring, and the mixture was reacted under heating under reflux (=2 hours).

The reaction product was concentrated to dryness under reduced pressure, the obtained crystalline material was washed with water, and the residue was purified using a column chroma dog 2 filter according to Example 2 to obtain 2-(benzenesulfony AI)-5-nitro -4-(trifluoromethyl)thiazole 1. Got Oj. Melting point 126-127°C.

The mass spectrum showed the same pattern as Example 2.

Production example 35% (wt) hydrobromic acid 360 j l2-2-amino-5-1-nitogastric-4-(triflucromethyl)F-7? /
- Add 23.1 N (0,108 moA/) and stir, heat for 10 minutes, cool with cryogen, and cool for 10 minutes.
C., copper powder 131 was added thereto, and then 33% sodium nitrite aqueous solution 40 F (0.18 mol) was added over 1 hour and 30 minutes to diazotize.

The reaction was stirred at room temperature for 1 h and then warmed to 40'C for 30
It lasted for a minute. This was cooled to -5°C (secondary), neutralized by adding a 30% aqueous sodium hydroxide solution, and extracted with react foam. The chloroform extract was washed with water, dried over anhydrous magnesium sulfate, and the chloroform was distilled off under reduced pressure. 2-Brom-
Crude product of 5-nitro-4-(trifluoromethyl)thiazole 24.3JF (yield 81, melting point 35-37°C, mass spectrum yM/e) i277M''.

)A plot 1-("" し し し し し し し し し し し し し し し し し し ます. Table 1 The following is a list of some test examples regarding the efficacy and toxicity of the antifungal agent of the present invention.

Test Example 10 Human pathogenic bacteria (2 types of antibacterial human pathogenic bacteria (Candida albicans IFO)
0579, Trichophyton mentagr
Ophytes IFO5811) was selected as the test bacterium, and its in vitro antibacterial properties were examined by the method described in a certain magazine 88,227 (196 g). The results are shown in Table 2).

Test Example 2゜Trichomonas (Frichamonas foetus)
) was selected as the test bacterium, and its in vitro antibacterial properties were examined using the method described in Parasitic Tsume, Vol. 11, p. 46,650 (1961). The results are shown in Table 2.

Test Example 3 The acute oral toxicity of the compound of the present invention to mice (dJ'ys male, 5 weeks old) was investigated. Oral acute toxicity tests were conducted by suspending the compound in a 0.5% CMC solution (5%
9/KIF was forcibly administered twice through the stomach tube. - LD, than weekly mortality rate. I asked for the range. The results are also listed in Table 2.

Table 2 (Means for Solving Problems - Agricultural and Horticultural Preparations) When the compound of the present invention is used as an agricultural chemical, it can be used in the following forms as general agricultural chemicals: wettable powders, granules, powders, emulsions, and water. It can be used in the form of a solvent, aerosol, etc. As additives and carriers, when the purpose is to make solids, vegetable powders such as soybean flour and wheat flour, diatomaceous earth, apatite, gypsum, Merck,
Fine mineral powders such as pyrophyllite and clay are used. For liquid formulation purposes, kerosene, ffi
Oil, petroleum, Tsurbentona 7F, xylene, cyclohexane, cyclohexamene, dimethylformamide, dimethyl sulfoxide, alcohol, acetone, water, etc. are used as solvents. If necessary, a surfactant may be added to these preparations to obtain a uniform and stable form.

The wettable powders and emulsions thus obtained are diluted with water to a predetermined concentration to form a suspension or emulsion, and the powders and granules are used as they are on plants (by a method of dispersing them).

Next, some formulation examples of the composition of the present invention will be shown, but the additives and addition ratios should not be limited to these formulation examples and can be varied within a wide range.

Formulation example 1. Hydrating agent compound 1 40 parts Diatom ±
53 parts Higher alcohol sulfate ester 4 parts Alkylnaphthazine sulfone f! By uniformly mixing 38 or more and pulverizing the mixture, a wettable powder containing 40% of the active ingredient can be obtained.

Formulation Example λ Emulsion Compound 7 20 parts Kikuren
38 parts dimethylformamide
If 35 parts polyoxyethylene alkyl prill ether 7 parts or more are mixed and dissolved, the active ingredient 2
If a 0% emulsion is uniformly mixed with 10 parts of Compound 3, 89 parts of Merck, and 1 part or more of polyoxyethylene alkyl allyl ether and finely ground, 10 parts of the active ingredient can be obtained.
Obtain % powder.

It goes without saying that the compound of the present invention is sufficiently effective when used alone, but it is insufficiently or weakly effective against pests and diseases other than those shown in the examples below, so various fungicides may be used to compensate for this. or insecticide/acaricide type 1 or 2
．． A test example regarding the bactericidal activity (for agricultural use) of the compound of the present invention will be shown as a convenient method by mixing it with 11 or more.

Test example 4. Apple apple seedlings grown in clay pots (variety ``Kunimitsu'', 3~
After spraying a predetermined concentration of a hydrating powder of the compound of the present invention at the 4-leaf stage) and air-drying it, the apple scab fungus (Venture
ia 1naequalis) inoculated with conidia,
kept in a greenhouse at 16°C and then in a greenhouse at 15-20°C
;I put it in there and got sick. Two weeks later: The degree of disease onset on each of the two leaves was investigated according to the investigation criteria, and the control value (%) of the treated area was calculated using the following formula. The results are shown in Table 3.

3rd table band 1: Commercially available product "Cabtan J 80% hydrating powder N-(trichloromethylthio)-4-cyclohexene-1,2-dicarboxylic acid test example 5. Seedlings were grown for about 3 weeks and disease control test Ichi Tameuri (variety "Sumo Hanpaku") seedling 1: Spraying a chemical solution of a predetermined concentration of a hydrating powder of the compound of the present invention,
After air-drying, a suspension of hypercircular zoospores collected from leaves infected with Chieculibe was spray-inoculated and kept in an inoculation box at 5°C and 100% humidity. 2 days after inoculation, the treated P. cucurbit seedlings were transferred to a greenhouse (23-28°C), and 7 days after inoculation, the severity of disease on each P. cucurbita leaf was investigated according to the following standards, and the number of treated plots was determined using the following formula. The control value (%) was calculated. The result is the fourth
Shown in the table.

Investigation standard lesion area (healthy x micro lesions) <5% x 0% x 5% z5
% 4 Table 4 #1: Commercially available product "Daconyl" 75% hydrating powder Tetranitrile 2: Commercially available product "Zinebdaisen" 72% permanent agent Zinc ethylene bisdithiocarbamate Test example 6. Sugar beet brown spot fungus spore germination inhibition test Sugar beet grown in clay pots (variety ``
Fresh lesions were selected from leaves affected by the main disease of young seedlings (4-5 leaf stage), and conidia were collected using sterile water. A hydrating agent containing the compound of the present invention was added to this conidial suspension at a predetermined concentration.

This treatment solution was dripped onto a 28'C14 slide glass.
After keeping it in a humid room for several days, it was examined using a microscope.

The germination inhibition rate for each treated plot was calculated based on the germination rate of conidia in the untreated plot. The results are shown in Table 5.

Table 5

Claims (4)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X is a halogen atom, lower alkyl group, trifluoromethyl group, or trifluoromethoxy group, m is 0,
1 or 2, and n represents 0 or 2. ). (2) 5-nitro-4-trifluoromethyl-2-halogenothiazole represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Y represents a halogen atom.) and the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, X is a halogen atom, lower alkyl group, trifluoromethyl group, or trifluoromethoxy group, and Z is SH
group or SO_2Na, m represents 0, 1 or 2. ) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X and m have the same meanings as above, and n indicates 0 or 2.) A method for producing a compound represented by (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X is a halogen atom, lower alkyl group, trifluoromethyl group, or trifluoromethoxy group, m is 0,
Indicates 1 or 2. ) is oxidized using an oxidizing agent ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X and m have the same meanings as above.) A method for producing a compound. (4) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A bactericide characterized by containing a compound represented by the following as an active ingredient.