CS235346B2 - Fungicide agent for plant or seeds treatment and method of efficient substances production - Google Patents

Abstract

A fungicidal agent for the treatment of plants or seeds, characterized in that the active substance contains a triazole derivative of formula (I) OH N ^ N-CH2-C (CF2) n-CF3 (I) = N I n in which R is phenyl, optionally substituted with one to three substituents independently of the one selected from the group consisting of fluorine, chlorine, bromine and iodine atoms and trifluoromethyl and n has a value of 0, 1 or 2, or an agricultural value thereof usable salt, along with agriculturally a suitable diluent or carrier.

Description

The present invention relates to novel triezole derivatives having antlfungal efficacy and useful for the treatment of fungal infections in animals, including humans, and as agricultural fungicides, as well as a process for the production thereof.

Accordingly, the invention provides a process for the preparation of compounds of formula (1)

(I) in which

R is phenyl optionally substituted with one to three substituents independently selected from fluoro, chloro, bromo and iodo and trifluoromethyl, and n is 0, 1 or 2, and pharmaceutically and agriculturally acceptable salts thereof.

The invention also includes a fungicidal plant and seed protection composition comprising a compound of formula (I) or an agriculturally acceptable salt thereof, together with an agriculturally useful diluent or carrier.

When R is the aforementioned optionally substituted phenyl group, it is preferably a phenyl group substituted with one to three, more preferably one to three, more preferably one or two substituents independently selected from the group consisting of fluorine, chlorine and iodine, and trifluoromethyl. Thus, the radical R in particular represents 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-fluoro-4-chlorophenyl, 2, A 5-difluorophenyl group,

2,4,6-trifluorophenyl or 4-bromo-2,5-difluorophenyl.

Most preferably, R is 2,4-dichlorophenyl or 2,4-difluorophenyl.

Most preferably, f is 0 or 1.

The compounds of formula (I) in which a has the value 0 may be prepared according to the invention according to the following reaction scheme:

CF ₃ COCH _2. Hal + (IV)

R.Li

OH

1,2,4-triazole, a base (e.g. ^k 2 ^CO 3 - temperature to 130 ° C, reaction time db 24 hours)

OH

In the above reaction scheme, Hal is chlorine or bromine.

Instead of 1,2,4-triazole and potassium carbonate, an alkali metal salt of 1,2,4-triazole can also be used, which can be prepared, for example, from sodium hydride and triazole.

According to a typical reaction, the haloketone of formula (IV) and the lithium derivative or Grignard reagent are stirred at -78 ° C for about 1 hour. for example in diethyl ether. Alternatively, the intermediate haloalkanol of formula (V) may be isolated by conventional means. The haloalkanol is then heated together with 1,2,4-triazole, for example in dimethylformamide, to a temperature of about 50 to 130 ° C in the presence of a base such as potassium carbonate for about 24 hours. The product of formula IA can then be isolated in a conventional manner.

Compounds of formula (I) above wherein n is 1 or 2 may be prepared by a method analogous to that described above for the preparation of compounds of formula (IA), (4). according to the following reaction scheme:

1,2,4-triazole

Hal.CH ₂ -C- (CF ₂ ) _n -C ₃ ^K 2 ^C ° 3 50-130 ° C

-CH

OH _12- c- (cF ₂ ) _n -CF ₃ R (IB)

In the formulas shown in this scheme, Hal is chlorine or bromine and has a value of 1 or 2.

This reaction is carried out under similar conditions to those described above, for example by heating in dimethylformamide to a temperature of about 130 ° C for about 24 hours. In this case too, the product can be isolated in a conventional manner. The starting materials can be prepared in a conventional manner, for example according to the following schemes:

(and)

BrCE ₃ (CH ₂ ) _n COCH ₃ concentrated

-> CF ₃ (CF ₂ ) _n COCH ₂ Br

H ₂ S ° 4 see J. Am. Chem. Soc., 22, 2,268-2,270 (1956)]

R.Li, R.MgBr or R.Ng1 -: ->

OH

AND

CH ₃ (CF ₂ ) _n -C-CH ₂ Br

R or (b)

Cgt ^ MgBr ^Cr 3 ^(CP 2 ^} n ¹ - * ^Cr 3 ^(CF 2> n ^MgBr

-78 ° C

OH

C1CH ₂ COR, -20 ° C ----- ClCH ₂ -C- (CF ₂ ) _n CF ₃

In this scheme, a is 1 or 2.

Pharmaceutically useful edition salts of the compound of formula (I) are those prepared with strong acids forming non-toxic acid addition salts of 3 acids such as hydrobromic acid, hydrochloric acid, sulfuric acid, oxalic acid and methanesulfonic acid.

These salts may be prepared in conventional manner, for example by mixing solutions containing equimolar amounts of the free base and the desired acid. The desired salt, if insoluble, is isolated by filtration or can be isolated by evaporation of the solvent.

Also included within the scope of the invention are alkali metal salts which can be prepared in a conventional manner.

The compounds of formula I and their pharmaceutically acceptable salts are antifungal agents which can be used to combat fungal infections in animals, including humans. For example, the compounds may be used to treat local fungal infections in humans caused, inter alia, by Candida, Trichophyton, Microsporum or Epidermophyton, or by mucosal infections caused by Candide albicans (e.g., oral and vaginal candidiasis). The disclosed compounds can also be used to treat systemic fungal infections caused by, for example, Candida albicans, Cryptococcus neoformans, Aapergillus fumigatus, Coccidioides, Paracoccidioides, Hetoplasma, or Blastomyces.

The in vitro evaluation of the antifungal activity of the disclosed compounds can be accomplished by determining the minimum inhibitory concentration (MIC), which is the concentration of the test compound in a suitable environment without growth of the respective microorganism. In practice, a series of agar plates, each containing the test compound at the appropriate concentration, is inoculated with a standard culture of, for example, Candida albicans, incubated at 37 ° C for 48 hours, after which the fungus growth (reep. absence of fungus) and the MIC value is determined. Other microorganisms which may be used include, for example, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton spec., Microsporum spec., Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata.

To evaluate the in vivo efficacy of the disclosed compounds, the compounds may be administered by intraperitoneal or intravenous injection or orally administered in a series of appropriately graduated doses to mice inoculated with Candida albicans. Efficacy is demonstrated by the survival of the treated group of mice after death of the untreated group of mice as assessed after 48 hours. The dose of the test compound which gives 50% protection against the lethal effect (ΡΒ ^ θ) is determined.

In the above assay, the following PD ^ q values (oral administration to mice against Candida albicans) were found:

Test substance PDj _Q ⁽ · ^ιη 8 / ^{ΐ £} β> oral)

The product of Example T1 0.1

0.1

1.5

1.5

0.1

1.1

0.1

0.15

0.2

Test substance

PDj0 (mg / kg, oral)

The product of Example 10 0.2 11 0.1 12 0.2 13 0.4 14 0.1 15 Dec 0.2

Preferred compounds are the products of Examples 1 and 8.

When used in human medicine, the antifungal compounds of formula (I) may be administered alone, but are generally administered in admixture with a pharmaceutical carrier selected taking into account the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing, for example, starch or lactose as carrier, or in the form of capsules or globules, either alone or in admixture with carriers or excipients, or in the form of elixirs or suspensions containing flavoring agents; dyes. Said compounds may further be administered parenterally. injections, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, the compounds of the invention are best used in the form of a sterile aqueous solution which may contain other substances, for example, an appropriate amount of salts or glucose to render the solution isotonic.

For oral and parenteral administration in human medicine, daily dosages (both oral and parenteral) of the antifungal compounds of Formula 1 range from 0.1 to 10 mg / kg (possible subdose administration). The tablets or capsules containing the active ingredient according to the invention will thus contain from 5 mg to 0.5 g of active ingredient for single, double or multiple administration per day, as appropriate in each case. In any case, the physician will determine the particular dosage which will be most appropriate for the patient and will vary depending on the age, weight and response of the patient to the formulation.

The above dosage is only an example of the average case and, of course, there may be individual cases in which higher or lower doses will have to be administered. All such cases are within the scope of the invention.

Alternatively, the antifungal compounds of formula I may be administered in the form of a suppository or peser, or administered topically in the form of a lotion, solution, cream, ointment, or powder. For example, the active ingredients may be incorporated into a cream made from a sophisticated emulsion of polyethylene glycols or liquid paraffin, or may be present at a concentration of between 1 and 10%. incorporated into a butter base consisting of white wax or white soft paraffin, optionally together with suitable stabilizers and preservatives.

The compounds of formula I and their salts also have activity against a wide variety of phytopathogenic fungi, including, for example, various rusts, mildews and molds, and can therefore be used to treat plants and seeds to prevent or treat these diseases.

The in vitro activity of the disclosed compounds against phytopathogenic fungi can be determined by measuring their minimum inhibitory concentrations in the same manner as described above except that the plates are incubated at 30 ° C for 48 hours or more before assessing the growth (or absence) of the fungus.

Microorganisms useful in these tests include Cochliobolus carbonum,

Pyricularia oryzae, Glomerella cingulata, Penicillium digitatum, Botrytis cinerea, and Rhizoctonia solani.

and

In the following! The results of the activity tests against phytopathogenic fungi carried out as described above are shown. These results are given in minimum inhibitory concentration (MIC) values in µm / ml.

Experimental fungi are identified by capital letters and the following meanings:

A = Glomerella cingulata

B = Helminthosporium carbonum

C = Penicillium digitatum

D = Botrytis cinerea

E = Pyricularia oryzae

The sign indicates that the test has not been performed in this case.

Tested substance (product from example #) MIC (µg / ml) against AND (B) C D E 1 0.8 3 0.8 0.8 6 2 50 100 ALIGN! 0.8 1.6 3 4 50 25 3 - 6 6 50 0.8 3 - 0.8 . 8 50 1.6 0.8 0.8 0.8 10 50 100 ALIGN! 0.8 0.8 1.6 12 25 1.6 0.8 - 1.6 13 100 ALIGN! 6 3 - 6 14 - 1.6 0.8 - 3

When used in agriculture and horticulture, the compounds of the invention and their agriculturally useful salts are preferably used in the form of compositions made with regard to the respective use and desired purpose. The compounds may be applied in the form of dusts or granules, seed dressings, aqueous solutions, dispersions or emulsions, wetting agents, sprayings, aerosols or smoke formers. These compositions may also be presented in the form of dispersible powders, granules or grains or concentrates to be diluted prior to use. Such compositions may contain conventional carriers, diluents or excipients as known and commonly used in agriculture and horticulture, and are manufactured in conventional manner. The disclosed compositions may also contain other active ingredients, for example compounds exhibiting herbicidal or insecticidal activity, or other fungicides. The compounds and compositions of the invention can be applied in a variety of ways, for example, directly to plant leaves, stems, branches, seeds or roots of plants, or to soil or other growth media, and can be used not only to treat disease but also prophylactically to protect plants or their seeds before the disease.

The invention is illustrated by the following non-limiting examples.

He did

Preparation of 2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -3,3,3-trifluoropropan-2-ol

^{1,2,4-triazol}

K2CO2

To 6 ml of diethyl ether was added 9.6 ml of a 1.55 M hexane solution of n-butyllithium (14.9 mmol), the resulting solution was cooled to -78 ° C and a solution of 3.03 g (15 ml) was added dropwise over 15 minutes. 7-mmol) of 2,4-difluorobromobenzene in 100 ml of diethyl ether and stirred at -78 ° C for 15 min. A solution of 2.4 g (12.6 mmol) of 1-bromo-3 is added dropwise over 15 min. 3,3-Trifluoropropan-2-one in 100 ml diethyl ether The mixture was stirred at -78 ° C for a further 30 minutes, then a solution of 2 ml glacial acetic acid in 5 ml diethyl ether was added, followed by 15 ml. The mixture was allowed to warm to 0 ° C, the aqueous layer was separated and washed with diethyl ether (2.times.30 ml). , 5 g (36.2 mmol) of 1,2,4-triazole and 10 g (72.5 mmol) of anhydrous potassium carbonate, the mixture is stirred it was heated 18 hours at 70 ° C, then cooled, poured into 150 ml water and extracted three times with 100 ml of ethyl acetate. The combined ethyl acetate extracts were washed with water (100 ml) and evaporated to dryness with magnesium sulfate. The residue was chromatographed on silica gel (230-400 mesh) using ethyl acetate / hexane (60:40 by volume) as eluent. Subsequent recrystallization from ethyl acetate / hexane gave 1.7 g (47%) of the title compound, m.p. 1.0-111 ° C.

For C 2,75HgFjN ^O requires C, 45.05; H, 2.75; N, 14.33.

Found: C, 45.16; H, 2.73; N, 14.56.

Examples 2 to 7

The compounds of the following Examples 2 to 7 were prepared by analogous methods to the previous examples using the appropriate arylllithium (Examples 2, 3, 5 and 6) or the Orignaid reagent (Examples 4 and 7) respectively. In Examples 4 and 6, tetrahydrofuran was used in place of dimethylformamide in the final reaction step.

OH F / N, N-C-CH.-CF \ / ² I ^{3 '== Z} NI

R

Example R Yield Temperature Analysis (%) - found (calculated) number <*> melting point (° C) C Η N

148-150

35.90 1.93 11.42 (35.51 1.90 11.29)

Br

Cl

94-96

134-136

89-91

144-147

44.36 2.76 13.13 (44.32 2.79 12.92) 47.78 3.20 15.49 (48,00 3.30 15.27) 42.77 2.27 13.88 (42.46 2.27 13.50) 37.19 3.04 10.67 (37.02 3.11 10.79) 43.4 2.7 13.0 (42.7 2.6 13.6)

Legend:

^χ ) as methanesulfonate

Example 8 (A) Preparation of 1-bromo-3,3,4,4,4-pentafluorobutanone

Br.

ct ₃ cf ₂ coch ₃ > řjCFgCOCHgBr

3.9 g (0.02407 mol) of methyl pentafluoromethylketone [j. Am. Chem. Soc. 78, 2,268-2,270 (1956) was stirred at room temperature under a solid carbon dioxide reflux condenser in 10 ml of concentrated sulfuric acid, then 1.92 g (0.012035 mol) was slowly added over 2 hours with vigorous stirring. bromine. The mixture was stirred at 50 ° C for 1 hour and the resulting amber solution was distilled at atmospheric pressure. One main fraction was obtained, weighing 4.41 g (76%), boiling at 94-97 ° C. The mass spectrum confirms this structure because it shows the presence of two molecular ions at 240 and 242, corresponding to C 1 BrF 4 O (two Br isotopes).

(B) Preparation of 2- (2,4-difluorophenyl) -3,3,4,4,4-pentafluoro-1- (1H-1,2,4-triazol-1-yl) butan-2-ol

N - NH

K ₂ CO ₃

3.32 ml of a 1.5 M hexane solution of n-butyllithium (0.00498 mol) in 5 ml of diethyl ether was cooled to -78 ° C with stirring and a solution of 1.0 g (0.00519 mol) was slowly added over 15 minutes.

2,4-difluorobromobenzene in 8 ml of ether. The reaction mixture was cooled to -78 ° C for 15 minutes, then 1.0 g (0.00415 mol) of 1-bromo-3,3,4,4,4-pentafluorobutanone was added over 15 minutes at -78 ° C. in 6 ml of ether. The mixture was stirred at -78 ° C for 30 minutes, then 0.7 g of acetic acid in 5 ml of ether was added, followed by 8 ml of water. The resulting mixture was allowed to warm to room temperature, the ether layer was separated and the aqueous layer was washed twice with 15 ml of ether each time. The combined ether layers were dried over magnesium sulfate and evaporated to an oily residue, to which were added 0.86 g (0.01245 mol) of 1,2,4-triazole, 5.73 g (0.0415 mol) of anhydrous potassium carbonate and 15 ml of anhydrous dimethylformamide. The reaction mixture was heated to 80 ° C with stirring for 3 1/2 hours, then cooled to room temperature and poured into 150 ml of water. The aqueous mixture was extracted three times with 60 ml of methylene chloride each time, the combined organic extracts were dried over magnesium sulfate and evaporated to a brown oily residue which was chromatographed rapidly on silica gel (230-400 mesh). Elution with a 60:40 by volume mixture of ethyl acetate and hexane gave 400 mg (28%) of the title compound as a white solid melting after crystallization from cyclohexane at 95-96 ° C.

Analysis:

calculated for C ₁₂ H _q F ₇ N ₃ O

% C, 42.0%;% H, 2.3%;% N, 12.2%;% C, 41.8%;% H; 2.3%;

Examples up to 13

The following compounds were prepared from the corresponding starting materials in an analogous manner to the preceding example:

\ = N

OH

AND

-ch ₂ —C — CF ₂ CF ₃ R

Example number

Yield Temperature (%) Melting (° C)

Analysis (%) - found (calculated) C H R

38.39

109-110 (38.32

34.32

168-170 (34.14

41.98

108-110 (41.61

44.3

95-97 (44.3

44.6

5.9 95-97 (44.3

2.12 11.12 2.14 11.17) 1.67 9.58 1.67 9,95) 2.42 11.16 2.42 11.20) 2.7 12.7 2.8 12,9) 2.8 13.3 2.8 12,9)

Example 1 a

2d Preparation 14, 4-difluorophenyl) -3,3,4,4,5,5,5-heptafluoro-1- (1H-1,2,4-triazol-1-yl) pentan-2-ol of smell _2c (CF _2, CF _{3 2} 'F

OH

OH

1,2,4-triazole

K ₂ CO ₃

F

To a solution of 5 g (0.017 mol) heptafluorpropyljodidu in 20 ml of ether, cooled to -78 ° C was added dropwise 5.6 ml of 3 M ethereal solution of phenylmagnesium bromide (0.017 mol) at such a rate that the temperature of the reaction mixture did not exceed -50 DEG C. After ^e the allocations věeho phenylmagnesium bromide, the mixture was stirred for 0.5 hours at -50 ° C and then recooled to -78 ° C and treated dropwise with Solutions of 3.6 g (0.019 mole) of 2-chloro-2 ^of 4 * 20 -diflueracetefenenu ml of ether at such a rate that the temperature of the mixture did not exceed -50 ° C. After the addition was complete, the reaction mixture was allowed to warm to -20 ° C and stirred at this temperature for 2 hours. about 5 ° C. The aqueous phase is separated, extracted twice with 50 ml of ether each time, the combined ether extracts are dried over magnesium sulphate and evaporated. 6.7 g of pale yellow oily material are obtained, which is added to a mixture of 5.87 g (0.085 mol) of 1,2,4-triazole and 17.5 g (0.127 mol) of anhydrous potassium carbonate in 60 ml of dimethylformamide. The reaction mixture was stirred at 80 ° C for 3 hours. After cooling, the dimethylfermamide was evaporated and the residue was partitioned between 200 ml of water and 150 ml of ethyl acetate. The aqueous layer was separated and extracted three times with 150 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed successively with aqueous sodium bisulfite solution and water, dried over magnesium sulfate, evaporated, and the residue was flash chromatographed on silica gel (230-400 mesh) using hexane / isopropyl alcohol / ammonium hydroxide (0.88 v / v). ratio of 80: 20: 1.5 as eluent.

Subsequent single recrystallization from hexane / dichloromethane gave 1.51 g of the title compound, m.p. 128 ° C. Yield 23%.

N, 10.7%. Found: C, 39.8%; H, 2.0%; N, 10.6%.

Example 15

In analogy to the previous example, 2- (4-fluorophenyl) -3,3,4,4,5,5,5-heptafluoro-1- (1H-1,2,4) is obtained from the appropriate starting material in 7% yield. -triazel-1-yl) pentan-2-el e melting point 126-127 DEG C. ^e

For C ^ HHgFgN ^O: C, 41.6; H, 2.4; N, 11.2.

found 41.9 ° C, 2.4% H, 11.3% N.

Claims (6)

OBJECT OF THE INVENTION A fungicidal composition for the treatment of plants or seeds, characterized in that it contains, as an active ingredient, a triazole derivative of the general formula 1 OH I (i) N N-CH ₂ -C- (CF ₂ ) _n -CF ₃ I 'in which R is a phenyl group optionally substituted with one to three substituents independently selected from the group consisting of fluorine, chlorine, bromine and iodine and trifluoromethyl aq is 0, 1 or 2, or an agriculturally acceptable salt thereof, together with an agriculturally useful diluent, or carrier. 23S346 2. A process for the preparation of triazole derivatives of the general formula I according to claim 1 and their salts, characterized in that 1,2,4-triazole or its alkali metal salt is reacted with a compound of the general formula VI OH Hal-CH ₂ -C- (CF ₂ ) _n -CF ₃ (VI) wherein Ran has the meaning given above and Hal represents chlorine or bromine, whereupon optionally the resulting product of formula (I) is converted into its salt in a conventional manner. 3. The process of claim 2 wherein the reaction is carried out either using 1,2,4-triazole in the presence of a base or using 1,2,4-triazole sodium. 4. A process according to claim 3, wherein the base is potassium carbonate. 5. A process according to any one of Claims 2 to 4, wherein the corresponding starting materials are used to form compounds of the general formula: ## STR4 ## wherein R is 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 2- fluoro-phenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl or 4-bromo-2,5- a difluorophenyl group of β and having a value of 0,1 or 2. 6. A process according to claim 2, wherein the corresponding starting materials are used to form compounds of formula (I) in which a is 0 and R is as in 1.