RU2051910C1 - (-) optically active derivative of triazolyl alcohol - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: the product: an (-) optically active derivative of triazolyl alcohol of the formula (I)

Description

(I) где Х означает атом водорода или атом хлора, а звездочкой показан асимметрический углеродный атом, которое может быть использовано в качестве фунгицидного активного ингредиента.The invention relates to an optically active derivative of a triazolyl alcohol having an optical activity (-) of the general formula (1):

(I) where X is a hydrogen atom or a chlorine atom, and an asterisk indicates an asymmetric carbon atom, which can be used as a fungicidal active ingredient.

Racemic derivatives of triazolyl alcohol and their fungicidal activities are known [1 and 2]
The triazolyl alcohol derivatives of the general formula (1) have optical isomers due to the asymmetric carbon atom (* C). The triazolyl alcohol derivative (1) having, as indicated above, optical activity (-). is an optical isomer that shows optical rotation (-) when measured in chloroform at a wavelength of the sodium spectral line D, and is called a (-) derivative of triazolyl alcohol. Salts of triazolyl alcohol derivatives are also included in the scope of the invention. These salts are acid salts that are physiologically tolerated by plants. Examples of such acids include hydrohalic acids, such as hydrobromic acid, hydrochloric acid and hydroiodic acid; carboxylic acids such as acetic acid, trichloroacetic acid, maleic acid and succinic acid; sulfonic acids such as para-toluenesulfonic acid and methanesulfonic acid; nitric acid, sulfuric acid and phosphoric acid. These salts are prepared in the usual manner.

 The usefulness of (-) - derivatives of triazolyl alcohol (I) was studied in detail and it was found that the fungicidal activity of the (-) - derivative of triazolyl alcohol is higher than the activity of its racemic derivative, while a completely new fact is discovered that, with respect to fungicidal activity (-) - derivatives exhibit exceptional properties.

 The invention makes a major contribution to limiting plant diseases or to cultivating more resistant plants in agriculture and horticulture. For example, the use of a more active chemical means is associated with the adequate application of a smaller amount of a chemical compound, which leads to an improvement in the economics of the processes of manufacture, transportation and use of chemicals in the fields, as well as to the expected reduction of environmental pollution to a minimum and to a greater safety of the drug. When using (-) - derivatives of triazolyl alcohol as a fungicide, no harmful effect on plants is observed, even if, due to improper use, an excessive amount of the compound and, therefore, it can be safely used to limit harmful plant diseases.

 Plant diseases that can be effectively controlled with (-) triazolyl alcohol derivatives include pyriculariosis and rice leaf sheath disease; plant cancer, flower rot, powdery mildew, scab, fruit blotch and fungal leaf blotch of apple trees; black spotting, powdery mildew, rust and scab of sand pear; melanosis, scab, anthracnose and ordinary green mold and blue citrus mold; brown peach rot; ripe rot, gray mold, real powdery mildew and rust of grapes; oat crown rust; powdery mildew, burns, striped leaves, loose smut, hard smut, snow rot and black rust of barley; brown rust, loose smut, stinky smut, leaf spot, spikelet spot, yellow rust, stem rust and real powdery mildew of wheat; powdery mildew, gray mold, sticky stem rot, sclerotin rot and anthracnose melons; leaf mold, real powdery mildew and early rot of tomatoes; gray mold, whorled wilting and real powdery mildew of eggplant; powdery mildew of allspice; gray mold and powdery mildew of the dugout; brown spotting and powdery mildew of tobacco; leaf spotting of sugar beets; and leaf spotting of peanuts.

 (-) - derivatives of triazolyl alcohol can be obtained by the methods used for known optically active substances, such as asymmetric reduction and isolation of the diastereoisomer obtained from racenate and an optically active reaction compound. These methods are described in detail below.

где Х атом водорода или хлора. Асимметрическое восстановление обычно осуществляют, используя энантиоселективную реакцию, которая происходит, когда катонное соединение (II) восстанавливают хиральным металло-водородным комплексом. Некоторые из таких способов описаны ниже.(1) Obtaining asymmetric recovery
A racemate of a compound of the invention is obtained by reducing a ketone compound of the general formula (II) with a metal-hydrogen complex, such as lithium aluminum hydride (LiAlH ₄ ) or sodium borohydride (NaBH ₄ ) [1]

where X is a hydrogen or chlorine atom. Asymmetric reduction is usually carried out using an enantioselective reaction, which occurs when the cationic compound (II) is reduced with a chiral metal-hydrogen complex. Some of these methods are described below.

 a) Typically, a chiral modified lithium aluminum hydride obtained by partial decomposition of lithium aluminum hydride with an optically active alcohol (Tetrahedron Letters Vol. 29, 913 (1973); Bull. Soc. Chem. Fr. 1968-3795; J. Org. Chem. 38 (10), 1973; Tetrahedron Letters 36, 3165 (1976).

 Among the examples of optically active alcohols used in the invention, (-) - menthol, (-) - borneol, (-) - methylephedrine and (-) - 2-N, N-dimethyl-amino-1- can be indicated as a source of asymmetry phenylethanol. You can use any of the optically active forms of other optically active alcohols, including alkaloid hydrocarbons and amino alcohols, such as, for example, quinine, cismurtanol, 2-N-benzyl-N-methylamino-1-phenyl-ethanol and 4-dimethylamino-3- methyl 1,2-diphenyl-2-butanol. The preparation of a chiral modified lithium aluminum hydride reductant using an optically active alcohol as an asymmetric source can be accomplished by adding 1-3 equivalent parts of optically active alcohol to one equivalent part of lithium aluminum hydride suspended in a suitable solvent. An ether, such as diethyl ether, tetrahydrofuran or dioxane, is usually used as a solvent, although an aromatic hydrocarbon such as benzene or toluene or an aliphatic hydrocarbon such as p-hexane or n-pentane can also be used. .

(III) где R² означает группу низшего алкила или фенильную группу, и одной эквивалентной части алюмогидрида лития Tetrahedron Letters том 21, 2753 (1980).В качестве примера оптически активного спирта, используемого как асимметрический источник по изобретению, можно привести любую из оптически активных форм оптически активного аминоспирта, такую, как, например, (-)-N-метилэфедрин или (-)-2-N,N-диметиламино-1-фенилэтанол. Что касается N-замещенного анилина, желательный результат получают при использовании анилина, замещенного низшим алкилом, такого, как N-метиланилин или N-этиланилин или дифениламин. Получение такого хирального модифицированного алюмогидрид-литиевого восстановителя можно осуществить путем суспендирования одной эквивалентной части алюмогидрида лития (LiAlH₄) в подходящем растворителе и смешивания с одной эквивалентной частью оптически активного спирта с последующим добавлением 2 эквивалентных частей N-замещенного анилина. Аналогично можно использовать растворитель, описанный выше в (а).c) It is sometimes advantageous to use a chiral modified lithium aluminum hydride reductant as a chiral metal-hydrogen complex obtained by reacting one equivalent part of optically active alcohol, 2 equivalent parts of an N-substituted aniline of the general formula (III)
H

(III) where R ² is a lower alkyl group or phenyl group, and one equivalent portion of Tetrahedron Letters lithium aluminum hydride volume 21, 2753 (1980). As an example of the optically active alcohol used as an asymmetric source of the invention, any of the optically active forms of an optically active amino alcohol, such as, for example, (-) - N-methylephedrine or (-) - 2-N, N-dimethylamino-1-phenylethanol. Regarding N-substituted aniline, the desired result is obtained using aniline substituted with lower alkyl, such as N-methylaniline or N-ethylaniline or diphenylamine. The preparation of such a chiral modified lithium aluminum hydride reductant can be accomplished by suspending one equivalent portion of lithium aluminum hydride (LiAlH ₄ ) in a suitable solvent and mixing with one equivalent portion of optically active alcohol, followed by 2 equivalent parts of N-substituted aniline. Similarly, you can use the solvent described above in (a).

Asymmetric reduction is carried out by adding a ketone compound (II) dissolved in a suitable solvent to a chiral modified lithium aluminum hydride obtained as described above in (a) or in (c). The solvent is used as described in (a). The reaction temperature is preferably ⁰ ° C or lower, despite the fact that it is possible to use a temperature of from -80 ^{° C} to the reflux temperature of the solvent. At the end of the reaction, the complex compound is decomposed by adding a dilute aqueous acidic solution, and the reaction mixture is purified by extraction, silica gel column chromatography or recrystallization to obtain the desired product.

(2) Obtaining by separation of diastereoisomers
A known method for the separation of optical isomers using diastereoisomeric esters obtained from a racemic alcohol compound and an optically active reaction compound (Org.Reaction volume 2, 380). A mixture of ester (IV) diastereoisomers is prepared by contacting a racemate of a triazolyl alcohol compound (1) with a reaction derivative of an optically active carboxylic acid in the presence of a base. The derivative of (-) - triazolyl alcohol (I) is obtained by separation of the indicated diastereoisomeric ester mixture by chromatography or fractional crystallization with the release of the ester of (-) - triazolyl alcohol and the subsequent decomposition of the specified ester.

(В вышеуказанных формулах Х и звездочка имеют вышеуказанные значения).

(In the above formulas, X and the asterisk have the above meanings).

 Examples of optically active carboxylic acids used to esterify a triazolyl alcohol racemate (I) are (-) - menthoxy acetic acid, (-) - N-trifluoroacetylproline, (-) - mandelic acid, (-) - 2-phenylpropionic acid, (- ) -2-isopropyl-4-chlorophenylacetic acid, (-) - α-methoxy-α-trifluoromethylphenylacetic acid, (-) - cis-chrysanthemum acid, and (-) - trans-chrysanthemum acid. The reaction derivatives of these optically active carboxylic acids include acid halides and anhydrides. Typically, the optically active carboxylic acid is converted to the acid halide in the usual manner and is contacted with a triazolyl alcohol (I) racemate to carry out the esterification. The reaction is carried out in an ordinary inert solvent (for example, in acetone, acetonitrile, tetrahydrofuran, in ethyl acetate, benzene, toluene, dichloromethane, in chloroform or in carbon tetrachloride) and in the presence of a reagent that cleaves hydrogen halide (for example, triethylamine, NN-dimethylaniline) . Typically, 1-5 moles of a carboxylic acid halide and a hydrogen halide cleaving reagent are used per mole of triazolyl alcohol racemate (I). Pyridine also behaves as a solvent if used in excess. The reaction temperature ranges from room temperature to the boiling point of the solvent. A diastereomeric ester can be prepared using an optically active carboxylic acid anhydride.

 If the diastereoisomeric triazolyl alcohol (V) ester mixture obtained as described above is capable of crystallization, it is separated by repeated fractional crystallization, although if it is in the form of an oil, separation is carried out by column chromatography using high speed liquid chromatography. The (-) - triazolyl alcohol ester thus obtained is decomposed in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water or an aqueous organic solvent (ethanol or methanol is usually used), to obtain a derivative of (-) - triazolyl alcohol (I).

 In field applications of the compounds of the invention obtained as described above, they can be used individually or with the addition of other ingredients, or in mixtures with a carrier, to make them more convenient for use as a fungicide. Examples of conventional forms of the preparation include dust, wettable powder, oily spray liquid, emulsion, tablet, granule, fine granule, spray, and the like. These preparations usually contain 0.1-95.0%, preferably 0.2-9.0 wt. active compound (including other active ingredients). A suitable application rate is 2-900 g / 10 acres, and a preferred concentration of the active ingredient for field application is 0.001-1.0%. However, the concentration can be suitably increased or decreased, without going beyond the specified range, since the application rate and concentration depends on the type of preparation , season, method of application, place of application, from a plant disease that needs to be suppressed, and the type of crop being treated.

 For use as a fungicide, the (-) - triazolyl alcohol derivative (I) can be mixed with other fungicides with, for example, N- (3,5-dichlorophenyl) -1,2-dimethylcyclopropane-1,2-dicarboximide , 3-n-butyl imido-ester-3-para-tert-butyl-benzyldithiocarboxylic acid, 0,0-dimethyl-0- (2,6-dichloro-4-methyl-phenyl) phosphorothioate, methyl 1-butylcarbamoyl-1H-benzimidazole -2-yl-carbamate, N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide, cis-N- (1,1,2,2-tetrachloroethylthio) -4-cyclohexene-1,2-dicarboximide, polyoxin , streptomycin, ethylene bis dithio-zinc carbamate, dime Zinc ilthiocarbamate, manganese ethylene bis dithiocarbamate, bis (N, N-dimethylthiocarbamoyl) disulfide, tetrachloroisophthalonitrile, 8-hydroxyquinoline, dodepyl-guanidinoacetate, 5,6-dihydro-2-methyl-1,4-oxathiinodio-3-carbide -N, N-dimethyl-N'-phenylsulfamide, 1- (4-chlorophenoxy) -3,3-dimethyl-1- (1,2,4-triazol-1-yl) -2-butanol, 1, 2-bis (3-methoxycarbonyl-2-thiourendo) benzene, methyl N- (2,6-dimethylphenyl) -N-methoxyacetyl-2-methylglycinate and aluminum ethyl phosphite.

 Further, (-) - a derivative of triazolyl alcohol (I) can be used in combination with other herbicides and plant growth regulators. Such a mixture does not reduce the inhibitory effect of each active component; on the contrary, a synergistic effect can be expected from the combined use. Examples of such reagents include phenoxy-type herbicides such as 2,4-dichlorophenoxyacetic acid, 2-methyl-4-chlorophenoxy-butyric acid, 2-methyl-4-chlorophenoxyacetic acid, and their esters and salts; defenyl ether type herbicides such as 2,4-dichlorophenyl 4'-nitrophenyl ether, 2,4,6-trichlorophenyl 4'-nitrophenyl ether, 2-chloro-4-trifluoromethylphenyl 3'-ethoxy-4'- nitrophenyl ether, 2,4-dichlorophenyl 4'-nitro-3'-methoxyphenyl ether, And 2,4-dichlorophenyl 3'-methoxycarbonyl-4'-nitrophenyl ether; triazine-type herbicides such as 2-chloro-4,6-bioethylamino-1, 3,5-triazine, 2-chloro-4-ethylamino-6-isopropylamino-1,3, 5-triazine, 2-methylthio-4 6-bis-ethylamino-1,3,5-triazine and 2-methylthio-4,6-bis-isopropylamino-1,3,5-triazine; urea-type herbicides such as 3- (3,4-dichlorophenyl) -1,1-dimethylurea, 3- (3,4-dichlorophenyl) 1-methoxy-1-methylurea, 1- (α, α-dimethylbenzyl ) -3-paratolylurea and 1- (2-benzothiazolyl) -1,3-dimethylurea; carbamate type herbicides such as isopropyl N- (3-chlorophenyl) carbamate and methyl N- (3,4-dichlorophenyl) carbamate; thiol carbamate type herbicides such as 3- (4-chlorobenzyl) N, N-diethylthiol carbamate and 3-ethyl N, N-hexamethylene thiol carbamate; acid anilide type herbicides such as 3,4-dichloropropionic anilide, 2-chloro-N-methoxymethyl-2 ', 6'-diethylacetanilide, 2-chloro-2', 6'-diethyl-N- (butoxymethyl) acetanilide , 2-chloro-2 ', 6'-diethyl-N- (p-propoxyethyl) acetanilide and N-chloroacetyl-N- (2,6-diethylphenyl) glypin ethyl ester; uracil type herbicides such as 5-bromo-3-sec-butyl-6-methyluracil and 3-cyclohexyl-5,6-trimethyleneuranyl; pyridinium salt type herbicides such as 1,1'-dimethyl-4,4'-bipyridinium chloride; phosphorus-type herbicides such as N- (phosphonomethyl) glycine, N, N-bis (phosphonomethyl) glycine, O-ethyl O- (2-nitro-5-methylphenyl) N-sec-butyl phosphoroamidothioate, S- (2- methyl-1-piperidylcarbonylmethyl) O, O-di-n-propyl-dithiophosphate and S- (2-methyl-1-piperidyl-carbonylmethyl) O, O-diphenyldithiophosphate; toluidine type herbicides such as α, α, α-trifluoro-2,6-dinitro-N, N-dipropyl-para-toluidyl; 5-tert-butyl-3- (2,4-di-chloro-5-isopropoxyphenyl) -1,3,4-oxadiazolin-2-one, 3-isopropyl- (1H) -2,1,3-benzothiazine- (3H) -one, 2,2-dioxide, α- (β-naphthoxy) propionanilide, 4- (2,4-dichlorobenzoyl) -1,3-dimethylpyrazol-5-yl para-toluenesulfonate; 3- (methoxycarbonylamino) - phenyl 3-methylphenyl-carbamate and 4-amino-3-methyl-6-phenyl-1,2,4-triazine. The invention is further illustrated by examples of the preparation of test and reference compounds.

 PRI me R 1. Synthesis of (±) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-pentene -3-ol by separation of the diastereoisomeric ester.

A mixture of 4.3 g of (-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3- ol and 8 g of (-) - mentoksiatsetilhlorida stirred in 50 cm ³ of pyridine at ⁷⁰ ° C for 7 hours The reaction mixture was poured into 200 ^cm3 of ice-water and extracted with 400 cm ³ of ethyl acetate.. The organic layer was washed successively with 0.5 N hydrochloric acid, 200 cm ^{3 of a} saturated aqueous solution of sodium bicarbonate and 200 cm ^{3 of} ice water, then dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting oily crude was purified by silica gel column chromatography (150 g of silica gel; developing solvent: n-hexane / acetone 30: 1) to obtain 7.4 g (±) - / (E) -1- (4-chlorophenyl) - 2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-yl / - (-) - menthoxy acetate. Repeat chromatography on another silica gel column (250 g silica gel; developing solvent: n-hexane / benzene / acetone 20/20/1), 2.6 g (-) - / (E) -1- (4-chlorophenyl) were obtained ) -2- (1,2,4-triazol-1-yl) - 4,4-dimethyl-1-penten-3-yl / - (-) - menthoxy acetate (n ²⁵ 1.5265), as the first eluate , 3 g of a diastereoisomeric ester mixture as a second eluate, and 1.2 g of (+) - / (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) - 4,4-dimethyl-1-penten-3-yl / - (-) - menthoxyacetate (n $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ 1.5265) as the first eluate 3 g. Diastereoisomeric ester mixture, as the second eluate, and 1.2 g (+) - / (E) -1- (4-chlorophenyl) -2- (1,2, 4-triazole) -1-yl) -4,4-dimethyl-1-penten-3-yl / - (-) - menthoxyacetate (n $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ 1.5281) as the final eluate.

Mixture of 2.6 g of (-) - / (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3- yl / - (-) - mentoksiatsetata 40 and 95 cm ³ of aqueous solution of ethanol containing 0.4 g of potassium hydroxide, stirred at 30 ^{° C} for 1 hour The reaction mixture was poured into 200 ^cm3 of ice-water and extracted with 300 cm ^3. ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude crystals obtained were recrystallized from a mixture of carbon tetrachloride-n-hexane to obtain 1.2 g.

(-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol; (α) ²⁴ 16.0 (s 1, CHCl ₃ ); Melting point 170-171 ° ^C. The NMR spectrum corresponded NMR spectrum of the racemate (compound 3).

 PRI me R 2. Synthesis of (-) - (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1 -penten-3-ol by separation of the diastereoisomeric ester.

A mixture of 4.0 g of (±) - (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten- 3-ol and 8 g of (-) - mentoksiatsetil- chloride is stirred in 50 cm ³ of pyridine at ⁷⁰ ° C for 7 hours The reaction mixture was treated following the procedure described in example 1. The resulting oily substance was purified by chromatography on a silica gel column (150. g of silica gel; developing solution: n-hexane / acetone 30: 1). Obtaining 5 g of (±) - / (E) -1- (2,4-dichlorophenyl) - 2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3- sludge - - (-) - methoxyacetate. Repeat chromatographic separation on another silica gel column (250 g silica gel; developing solution: n-hexane / benzene / acetone 20/20/1). 1.6 g of (-) - / (E) - (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3- were obtained sludge - - (-) - menthoxyacetate (n $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ 1.5172) as the first eluate, 2 g of the diastereoisomeric ester mixture as the second eluate and 0.7 g of (+) - / (E) -1 (2,4-dichlorophenyl) -2- (1,2,4- triazol-1-yl) -4,4-dimethyl-1-penten-3-yl / - (-) - menthoxyacetate (n $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ 1.5102) as the final eluate.

A mixture of 1.6 g of (-) - / (E) -1- (2-, 4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1- penten-3-yl / - (-) - mentoksiatsetata and 30 cm ³ of 95% aqueous ethanol containing 0.2 g of potassium hydroxide, stirred at ²⁵ ° C for 1 hour The reaction mixture was poured into 200 cm ³ of ice. water and was extracted with 300 cm ³ ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, (-) - (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4, 4 - dimethyl-1-penten-3-ol: n $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 31.7 (c = 1, _CHCl3), melting point 160-161 ^° C NMR spectrum corresponded NMR racemate (compound 4).

 PRI me R 3. Asymmetric recovery using (+) - menthol.

To a mixture of 0.4 g (0.01 mole) LiAlH ₄ and 30 cm ³ of tetrahydrofuran was added at 10 ^C. 30 cm ³ of tetrahydrofuran solution containing 4.4 g (0.028 mol) of (+) - menthol. To the mixture, which was stirred at room temperature for 30 min, added at (-30) ^C. 50 cm ³ of tetrahydrofuran solution containing 2.0 g (0.007 mol) of 1- (4-chlorophenyl) -2- (1,2 , 4-triazol-1-yl) -4,4-dimethyl-1-penten-3-one. The resulting mixture was stirred for 2 hours, maintaining the temperature at (-5) ° ^C. After the addition of 5 cm ³ of 1N hydrochloric acid, the insolubles were removed by filtration and the filtrate was poured into 300 ^cm3 of ice-water and extracted with 500 cm ³ of ethyl ether. The organic layer was washed successively with 200 cm ^{3 of a} saturated aqueous solution of sodium bicarbonate and 200 cm ^{3 of} ice water. The washed organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product as an oil. The crude product was purified by silica gel chromatography (100 g of silica gel; developing solvent: n-hexane / acetone 30: 1), whereby 0.5 g of unreacted ketone starting material and 1.0 g of crystals were isolated (after crystallization from a mixture of carbon tetrachloride-n -hexane) (-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol. (α) $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ 6.0 (c1, CHCl ₃ ).

 PRI me R 4. Asymmetric recovery using (+) - 2-N, N-dimethylamino-1-phenylethanol.

To a mixture of 0.4 g of LiAlH ₄ and 20 cm ^{3 of} ethyl ether under ice cooling was added dropwise 50 cm ^{3 of an} ether solution containing 1.75 g of (S) -2-dimethylamino-1-phenylethanol. Upon completion of the addition, the mixture was stirred for 15 minutes in the absence of cooling. To the mixture was added dropwise 20 cm ^{3 of an} ethereal solution containing 2.54 g of N-ethylaniline. After addition, the mixture was stirred for 3 hours at room temperature. To the mixture was added dropwise at (-70) ^C. 50 cm ³ of ether solution containing 1.13 g of (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1- yl) -4,4-dimethyl-1-penten-3-one. The mixture was stirred for 3 hours at (-73) ^{° C,} and then left to stand overnight at room temperature. To the mixture was added 110 cm ^{3 of} 2 N hydrochloric acid to effect decomposition. The organic layer was separated, washed successively with 100 cm ^{3 of a} saturated aqueous solution of sodium bicarbonate and 100 cm ^{3 of} ice water, then dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 1.26 g of a crystalline compound of triazolyl alcohol: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 16.6 (s 1.0, CHCl ₃ ). The crystalline compound was recrystallized from a mixture of cyclohexane-methanol to obtain 0.4 g of (-) - (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4, 4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 28.8 (s 1.0, CHCl ₃ ), melting point 160-161 ^about C.

 PRI me R 5. Asymmetric recovery using (+) - 2-N-benzyl-N-methylamino-1-phenylethanol.

To a solution of 1.08 g (0.0284 mol) of LiAlH ₄ in 85 cm ^{3 of} ethyl ether, 22 cm ^{3 of an} ether solution containing 6.86 g (0.0284 mol) was added dropwise under ice cooling. (+) - 2-N-benzyl-N-methylamino-1-phenylethanol and then 40 cm ^{3 of an} ether solution containing 6.90 g (0.0564 mol) of N-ethylaniline. After stirring at room temperature for 3 hours, the mixture was cooled to (-78) ^° C, containing 2.75 g (0.0095 mol) to the mixture was added dropwise 55 cm ³ of ether solution of (E) -1- (4 -chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-one. The mixture was stirred at the indicated temperature for 3 hours and left to stand overnight at room temperature. Then to the mixture was added 105 cm ³ 2 N. hydrochloric acid to effect decomposition. The organic layer was separated, washed successively with 100 cm ^{3 of a} saturated aqueous solution of sodium bicarbonate and 100 cm ^{3 of} ice water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2.83 g of a crude product: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 6.44 (c 1.05 CHCl ₃ ). 2.8 g of a sample of the crude product were recrystallized three times from a mixture of cyclohexane-methanol to obtain 0.82 g of (-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl ) -4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 14.9 (c1.0, CHCl ₃ ).

 PRI me R 6. Asymmetric recovery using (+) - N-methyl ephedrine.

To a solution of 1.25 g (0.033 mol) of LiAlH ₄ in 40 cm ^{3 of} ethyl ether under ice cooling was added dropwise 100 cm ^{3 of an} ether solution containing 6.1 g (0.034 mol) of (+) - N-methylephedrine over 30 min After addition, the mixture was stirred for 15 minutes, keeping the temperature constant. Then, 45 cm ^{3 of an} ethereal solution containing 8.24 g (0.068 mol) of N-ethylaniline was added dropwise to the mixture over 30 minutes. After addition, the mixture was stirred for 2 hours at room temperature. Then, 60 cm ^{3 of an} ethereal solution containing 2.9 g (0.01 mol) (E) -1- (4-chlorophenyl) -2- (1,2,4-triazole-1-) were added to the mixture over 15 minutes il) -4,4-dimethyl-1-penten-3-one at a temperature of (-70) ^o C (-60) ^o C. The mixture was left to stand for 4 hours, maintaining the temperature at (-73) ^o C, and then mixed with 110 cm ³ 2 N. hydrochloric acid to effect decomposition. The organic layer was separated, washed successively with 100 cm ^{3 of a} saturated aqueous solution of sodium bicarbonate and 100 cm of ice water, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2.9 g of crystals of a triazolyl compound: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 10.1 (s 1.0, CHCl ₃ ). 2.5 g of a sample of crystals were recrystallized twice from a mixture of cyclohexane-dioxane to obtain 0.7 g of (-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 15.8 (c 1.0 CHCl _3), melting point 170-171 ° ^C.

 PRI me R 7. Synthesis of (-) - (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl - 1-penten-3-ol.

In 10 cm ^{3 of an} ether solution containing 0.18 g (4.7 mmol) of LiAlH ₄ , 10 cm ^{3 of an} ether solution containing 0.84 g (4.7 mmol) was added dropwise over 30 minutes at room temperature (+ ) -N-Methylephedrine and the mixture was stirred for 20 minutes. Under ice-cooling, 10 cm ^{3 of an} ether solution containing 1 g (9.4 mmol) of N-methylaniline was added dropwise to the mixture over 30 minutes, and the mixture was stirred for 1 h at room temperature. To the reaction mixture, cooled to (-15) ^° C, 10 cm ^{3 of an} ethereal solution containing 1 g (3.1 millimoles) (E) -1- (2,4-dichlorophenyl) -2- ( 1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-one, and the mixture was stirred for 2 hours at (-15) ° ^C. The mixture was then poured into 100 cm ³ of 1 n hydrochloric acid, extracted with 100 cm ^{3 of} ether, washed sequentially with an aqueous solution of sodium bicarbonate and ice water, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. A crystalline precipitate was collected by filtration using 10 cm ^{3 of} n-hexane for washing, obtaining 0.98 g (98% yield) of the isolated compound (α) $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ 28.0 (s 1, chloroform).

 The NMR spectrum corresponds to the NMR spectrum of the racemate (compound 4).

 PRI me R 8. Asymmetric recovery using (+) - N-methyl-ephedrine.

In a solution of 1.25 g (0.033 mol) of LiAlH ₄ in 40 cm ^{3 of} n-hexane, cooled in ice, 100 cm ^{3 of a} solution of n-hexane containing 6.1 g (0.034 mol) of (+) - N-methylephedrine are introduced into in the form of drops for 30 minutes After this input, the mixture is stirred for 15 minutes, keeping the temperature constant. Then, 45 cm ³ of a n-hexane solution containing 8.24 g (0.068 mol) of N-ethylaniline was added dropwise to the mixture over 30 minutes. After this input, the mixture was stirred for 2 hours at room temperature. Then, 60 cm ^{3 of a} solution of n-hexane containing 2.9 g (0.01 mol) (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) is introduced into the mixture -4,4-dimethyl-1-penten-3-one for 15 min at (-70) ^о С - (- 60) ^о С. The mixture stands for 4 hours at (-60) ^о С and then it is mixed with 110 cm ³ 2 N. hydrochloric acid for the purpose of decomposition. The organic layer was separated, washed successively with 100 cm ^{3 of a} saturated aqueous solution of sodium sulfate and evaporated in vacuo, resulting in 3.0 g of crystalline triazolyl compound (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 8.7 (with 1.0 CHCl ₃ ). 2.5 g of these crystals were recrystallized twice from a mixture of cyclohexane dioxane to obtain 0.5 g of (-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) - 4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 13.5 (c 1.0, CHCl ₃₎ Melting point 170-171 ° ^C.

 Using the methods described above, the following compounds are prepared.

 Compound 1.

(-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol:
(α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 16.0 (s 1, CHCl ₃ ); melting point 170-171 ^about C.

 NMR spectrum such as for racemate compound 5.

 Compound 2.

(-) - (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 31.7 (s 1, CHCl ₃ ), melting point 160-161 ^about C.

 The NMR spectrum is the same as the spectrum of the racemate compound 6.

 Compound 3.

Racemat (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-one: melting point 153-155 ^о С .

Elemental analysis: C% H% N% Cl%
Calculated for C ₁₅ H ₁₈ N ₃ OCl 62.17 5.58 14.50 12.23 Found 62.32 5.60 14.41 12.20
NMR spectrum.

 8.11 (1H, singlet, proton, triazole), 7.90 (1H, singlet, triazole proton), 7.15 (4H, singlet, phenyl proton), 6.99 (1H, singlet, olefin proton), 0 99 (9H, singlet, butyl proton).

(E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol:
Elemental analysis: C% H% N% Cl%
Calculated for C ₁₅ H ₁₈ N ₃ OCl 61.74 6.23 14.40 12.15 Found 61.82 6.38 14.38 12.15 NMR spectrum:
8.52 (1H, singlet, triazole proton), 7.98 (1H, singlet, triazole proton), 7.30 (4H, singlet, phenyl proton), 6.91 (1H, singlet, olefin proton), 4, 56 (2H, broad singlet, hydroxyl proton and proton of a methine group carrying a hydroxyl group); 0.66 (9H, singlet, butyl proton).

 Compound 4.

Racemate (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol: melting point 148-149 ^about S.

 8.45 (1H, singlet, triazole proton), 7.97 (1H, singlet, triazole proton), 7.80 (3H, multiplet, phenyl proton), 6.80 (1H, singlet, olefin proton), 4, 35 (2H, broad singlet, hydroxyl proton and methine proton carrying a hydroxyl group). 0.63 (9H, singlet, tert-butyl proton).

 Compound 5.

(-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazole) - 1-yl) -4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ 6.0 (s 1, CHCl ₃ ). (Obtained by asymmetric reduction of (+) - methanol).

 Compound 6.

(-) - (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-tri-azol-1-yl) -4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 28.8 (c = 1.0, _CHCl3), melting point 160-161 ^{° C,} obtained by asymmetric reduction with (+) - 2-N, N-dimethylamino-1-phenylethanol.

 Compound 7.

(-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 14.9 (s 1.0, CHCl ₃ ). (Obtained by asymmetric reduction of (+) - 2-N-benzyl-N-methylamino-1-phenylethanol.

 Compound 8.

(-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 15.8 (c = 1.0, _CHCl3), melting point 170-171 ^{° C} (prepared by asymmetric reduction of (+) - N-methylephedrine).

 Compound 9.

a) (-) - (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ -28.0 (s 1, chloroform).

c) (-) - (E) -1- (2,4-dichlorophenyl) -4,4-dimethyl-2- (1,2,4-triazol-1-yl) - 1-penten-3-ol, (α) $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ 27.0 (s 1, chloroform).

 Compound 10.

(-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ 5.0 (c 1, CHCl ₃ ) (comp. 5).

 Compound 11.

Asymmetric reduction using (+) - N-methylephedrine. (-) - (E) -1- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -4,4-dimethyl-1-penten-3-ol: (α) $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ 13.5 (c1.0; CHCl ₃ ), melting point 170-171 ^about C.

 The beneficial properties of the (-) - derivatives of the triazolyl alcohol according to the invention are illustrated below in detail with reference to some examples of tests carried out for (-) - (E) - (4-chlorophenyl) -2- (1,2,4-triazole-1- il) -4,4-dimethyl-1-penten-3-ol (compound 1) and for (-) - (E) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazole -1-yl) -4,4-dimethyl-1-penten-3-ol (compound 2) using, as reference samples, the corresponding racemates indicated above as compounds N 3 and N 4.

 AND S P T A T E L N Y P R I M E R 1. Inhibition of fungal growth.

Heated medium containing 5 g of polypeptone, 20 g of malt extract, 20 g of sucrose and 20 g of agar per 1 liter of water to obtain a liquid solution. A predetermined amount of a diluted sample of the test compound in the form of an emulsifiable concentrate was added to the fluidized medium in order to maintain the concentration of each sample in the medium at a predetermined level. After thorough mixing, the medium was poured into a Petri dish to obtain an agar plate. After the agar hardened, it was infected with a suspension of a colony or conidia of the studied fungi. The types of fungi and the time of the incubation period (the period from infection to observation) were as shown below. The incubation temperature of 20 ^{° C} for Venteria indequalu and 28 ^{° C} for other fungi.

Type of fungus Shortening Period
incubation
(days)
Helucinttu-
sporium granuneum Hg 6 Penicillium italicum Pi 6 Venturia muequalis Vi 7 Valsa mali Vm 4 Mycosphaerella melouis Mm 4 Diaporhe citri Dc 6 Ustilago nuola Un 6 Verticillium alboctrum Va 7 Septoria trihci St 7 Cercospora beticola Cb 7
The fungal growth inhibition activity of the test compound was evaluated by the concentration at which 90% mycelial growth is suppressed (ED ₉₀ ). As can be seen from the results given in table. 1, the triazolyl alcohol derivatives of the invention (compounds 1 and 2) have a significantly better antifungal spectrum of activity compared to (+) triazolyl alcohol derivatives (compounds 3 and 4) and with racemates (compounds 5 and 6).

 I N P T I T E L N Y P R I M E R 2. The effect of limiting leaf spotting of peanuts.

85-ml plastic pot filled with sandy loam, sowed peanut (cv semi-erect) at a rate of 1 seed per pot, and the seeds were grown in a greenhouse with an air-conditioned at 25-30 ^{° C} for 12 days, young seedlings received groundnut grown to the stage of the third sheet. At this stage, foliage was sprayed with an emulsified concentrate of each test compound at a rate of 10 ml / pot. After air drying, the seedlings were infected Cersospora personata, then the cover sheet and polyvinyl chloride film to maintain the humidity, and left standing in a greenhouse with an air-conditioned at 25-30 ° ^C. In order to fully manifest the disease, the seedlings were cultivated for further 10 days at specified greenhouse. Then, the foliage of each seedling was examined to determine the symptoms of the disease and the degree of the disease was calculated as follows: the appearance of damage on the examined leaf was evaluated by one of five indices, i.e. 0, 0.5, 1, 2, and 4, and the degree of disease was calculated using the equation below. Index Type of damage, damage 0 No colony visible
no damage. 0.5 On the surface of the sheet
colonies or damage
on an area of less than 5% of
full sheet area. 1 On the surface of the sheet
colonies or damage
to sites less than 20% of
full sheet area. 2 On the surface of the sheet
visible colonies or
damage to the area
less than 50% of full
sheet area. 4 On the surface of the sheet
visible colonies or
damage to the area
over 50% of dense
sheet area.

Затем рассчитывали контрольное зна- чение по следующему уравнению:
Контрольное значение (%) 100

× 100
Как видно из данных табл. 2, результаты испытания показывают, что (-)-производное триазолилового спирта обладает намного более сильным эффектом ограничения по сравнению с рацематом.The degree of disease (%)

Then, the control value was calculated by the following equation:
Reference value (%) 100

× 100
As can be seen from the data table. 2, the test results show that the (-) - triazolyl alcohol derivative has a much stronger restriction effect than the racemate.

EXPLANATORY EFFICIENCY 3. Effect of limiting brown rust of wheat (therapeutic effect) in a test on young seedlings:
85 ml plastic pot filled with sandy loam, wheat sown seeds (variety: Norin 61 N) at a rate of 10-15 seeds per pot, and seedlings were cultivated for 7 days in a greenhouse with an air-conditioned at 18-23 ^{° C} to grow young wheat seedlings to the stage of growth of the first leaves. At this stage, the seedlings were infected Puccimrecondita and allowed to stand in a humidified chamber at 23 ^{° C} for 16 hours so that they were infected with fungus. Then the plants were sprayed with a diluted emulsion of the test compound at a rate of 10 ml per pot. The pot with seedlings was kept in a thermostatic chamber at ²³ ° C, cultured for 10 days under irradiation with fluorescent lamps and responsive disease symptoms on the first leaf. The method for evaluating the symptoms and the method for calculating the control value were the same as in Test Example 2.

 As can be seen from the data in Table 3, the test results show that the (-) - derivative of triazolyl alcohol exhibits a much higher therapeutic effect compared to the racemate.

I S P T A T E L N Y P R I M E R 4. The effect of limiting apple scab (therapeutic effect) in the test on seedlings:
85-ml plastic pots filled with sandy loam, sowed 2 or 3 apple seeds and cultured in a conditioned chamber at 23-28 ^{° C} for 30 days the seedlings received in stages from the fifth to the sixth sheet. Seedlings at this stage were infested Venturia inalqualis and left standing in a humidified dark chamber (relative humidity 90% or higher) at ¹⁵ ° C, so that they were infected with fungus. Four days after this, the foliage was sprayed with an aqueous diluted liquid of the test compound in the form of an emulsifiable concentrate, which was applied at a rate of 10 ml per pot. The pot was 20-21 days in a temperature-controlled chamber at 15 ° ^C under light and moisture. Then the foliage was examined to determine the symptoms of the disease. Determining the degree of disease and calculating the control value was carried out in the same way as in test example 2.

 As can be seen from the data table. 4, the test results show that the therapeutic effect of the (-) - triazolyl alcohol derivative was much higher than the therapeutic effect of the racemate.

I N P T A T E L N Y P R I M E R 5. Testing the slowdown of wheat growth:
85-ml plastic pot filled with sandy loam, wheat planted 10-15 seeds (variety Chikugo N 2), which have been impregnated with a dilute aqueous solution of the test compound formulated in an emulsifiable concentrate and the seeds were cultivated at a controlled temperature of 18-23 ^{° C} for 7 days . Then, the sheet length was measured and percent elongation was determined by comparison with the sheet length in the control pot.

× 100
Результаты испытания приведены в табл.5. Было найдено, что активность замедления роста растения (-)-производного триазолилового спирта намного ниже, чем соответствующая активность рацемата.Elongation,

× 100
The test results are shown in table.5. It was found that the activity of slowing the growth of a plant (-) - a triazolyl alcohol derivative is much lower than the corresponding activity of the racemate.

Claims (1)

(-) OPTICALLY ACTIVE DERIVATIVE OF TRIAZOLYL ALCOHOL of the general formula

where X is hydrogen or chlorine;
an asterisk indicates an asymmetric carbon atom.

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