RU2116304C1 - Derivatives of azole, method of their synthesis, pharmaceutical composition - Google Patents

Abstract

FIELD: organic chemistry, heterocyclic compounds. SUBSTANCE: invention relates to the new derivatives of azole of the general formula (I):

where Ar -halide; R¹ - - hydrogen or lower alkyl; R³ - - lower alkyl possibly substituted with lower alkyl, halide, trifluoromethyl, lower alkoxy, halide (lower)-alkoxy, piperazinyl, benzylpiperazinyl, lower acylpiperazinyl, lower alkoxyphenylpiperazinyl being alkyl moiety of that can be substituted with halide, and Y and Z are independently nitrogen atom or methyne-group that can be optionally substituted additionally with lower alkyl-group, or its acid-additive salts exhibiting antifungal activity, and pharmaceutical composition based on thereof. The indicated compounds are synthesized by interaction of compounds of the formula (II)

and (III)

Description

 The invention relates to derivatives of azole used as antifungal therapeutic agents and to their use.

 Various derivatives have already been declared as antifungal agents (for example, EPA-122693, EPA-122056 and EPA-332387). These compounds, however, are not satisfactory in their therapeutic effect in terms of antifungal activity, spectrum of antifungal activity, side effects and pharmacokinetics.

 Traditional antifungal drugs do not have a sufficient therapeutic effect, and there are also many problems with side effects, pharmacokinetics, superinfection, and acquired resistance to drugs.

 To solve these problems, it is clear that compounds with a high degree of safety, better in vivo absorption, and stronger antifungal activity are desirable as therapeutic agents.

где
Ar является дизамещенной галоидом фенильной группой;
R¹ является водородным атомом или низшей алкильной группой;
R³ представляет низший алкил, возможно замешенный галоидом, фенил, незамещенный или замешенный низшим алкилом, галоидом, трифторметилом, низшим алкокси, галоид (низшим) алкокси, пиперазинилом, бензилпиперазинилом, низшим ацилпиперазинилом, низшим алкоксифенилпиперазином, алкильная часть которого может быть заменена галоидом, пиридил или пиримидинилрадикал;
X является атомом азота или метиновой группой; и
Y и Z независимо являются атомом азота или метиновой группой, которая необязательно может быть дополнительно замещена низшей алкильной группой,
или его кислотноаддитивным солям.The invention relates to an azole derivative of the formula (I)

Where
Ar is a halogen disubstituted phenyl group;
R ¹ is a hydrogen atom or a lower alkyl group;
R ³ represents lower alkyl, possibly mixed with halogen, phenyl unsubstituted or mixed with lower alkyl, halogen, trifluoromethyl, lower alkoxy, halo (lower) alkoxy, piperazinyl, benzylpiperazinyl, lower acylpiperazinyl, lower alkoxyphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenrazyl or pyrimidinyl radical;
X is a nitrogen atom or a methine group; and
Y and Z are independently a nitrogen atom or a methine group, which optionally can be further substituted with a lower alkyl group,
or its acid addition salts.

 The invention further provides an antifungal drug, which comprises an azole derivative represented by the formula (I), or a salt thereof.

The compound of formula I or a salt thereof according to the invention has one or more asymmetric carbon atoms in the molecule, thus has two or more stereoisomers. Some of these stereoisomers, as well as their mixture, are within the scope of the invention. As for the optical isomers, it is preferable when the carbon to which the substituted phenyl, denoted by Ar, is attached and the carbon to which R ₁ is attached have an R configuration.

где значения радикалов определены, как указано выше, с соединением формулы (III)

где значения радикалов определены, как указано выше, или его солью.A compound of formula I or a salt thereof according to the invention can be obtained, for example, by reaction of a compound of formula (II)

where the meanings of the radicals are determined, as indicated above, with a compound of formula (III)

where the meanings of the radicals are defined as indicated above, or a salt thereof.

 Said reaction can usually be carried out in a solvent which does not interfere with the reaction. Examples of such a solvent may be: water; ketones, such as acetone; sulfoxides, such as dimethyl sulfoxide; esters, such as diethyl ether, tetrahydrofuran or dioxane; nitriles, such as acetonitrile; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; esters such as ethyl acetate; amides, such as dimethylformamide, acetamide or dimethylacetamide; urea derivatives such as 1,3-dimethyl-2-imidazolidinone; etc. The solvent can be used either individually or as a mixture of solvents taken in a suitable ratio.

 Preferably, said reaction proceeds in the presence of a base such as an alkali metal hydroxide (e.g., lithium hydroxide, potassium hydroxide or sodium hydroxide), an alkali metal hydride (e.g., potassium hydride or sodium hydride), an alkali metal carbonate (e.g., lithium carbonate sodium bicarbonate, cesium carbonate, potassium carbonate or sodium carbonate), an organic acid salt (e.g. sodium acetate), an alkali metal alcoholate (e.g. sodium methylate or potassium tert-butylate), tetrabutyl fluoride mmoniya, bis (tri-n-butylstannyl) oxide, and the like

 Instead of a compound of formula III, a salt thereof with a metal (for example, an alkali metal such as sodium or potassium) can be used and the reaction is carried out in the specified solvent to obtain the desired compound.

 The amount of base used is usually 0.001-100 equivalents, preferably about 0.01-50 equivalents. relative to the compounds of formula (II).

 The amount of the compound of formula (III) or its salt is 1-100 equivalents, preferably about 1-50 equivalents. relative to the compounds of formula (II).

The reaction temperature is not particularly limited, but can usually be about 0-150 ^° C., preferably about 10-120 ^° C.

 The reaction time is usually from several minutes to several tens of hours (for example, from 5 minutes to 50 hours).

где значения радикалов определены, как указано выше, или его соли с соединением формулы (V)

где значения радикалов определены, как указано выше, или его соли.The compound of formula I according to the invention can also be obtained, for example, by reaction of a compound of formula (IV)

where the meanings of the radicals are defined as described above, or its salt with a compound of formula (V)

where the meanings of the radicals are defined as indicated above or a salt thereof.

 Said reaction can usually be carried out in a solvent which does not affect the reaction. Examples of such solvents are: water; ketone, such as acetone; sulfoxide, such as dimethyl sulfoxide; esters, such as diethyl ether, tetrahydrofuran or dioxane; nitrile, such as acetonitrile; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; esters such as ethyl acetate; amides, such as dimethylformamide, acetamide or dimethylacetamide; a urea derivative such as 1,3-dimethyl-2-imidazolidinone; etc. They can be used both individually and as a mixture, taken in a suitable ratio.

 Preferably, the reaction is carried out in the presence of a base such as an alkali metal hydroxide (e.g., lithium hydroxide, potassium hydroxide or sodium hydroxide), an alkali metal hydride (e.g., potassium hydride or sodium hydride), an alkali metal carbonate (e.g., lithium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate or sodium carbonate), an organic acid salt (e.g. sodium acetate), an alkali metal alcoholate (e.g. sodium methylate or potassium tetrabutylate), tetrabutylammonium fluoride etc.

 The amount of base is usually about 0.01-100 equivalents, preferably about 0.01-50 equivalents. in relation to the compound of formula (IV).

 The amount of the compound of formula (V) or its salt with respect to the compound of formula (IV) or its salt is 1-100 equivalents, preferably about 1-50 equivalents.

The reaction temperature is not specifically limited, but may be of the order of typically 0-150 ^° C., preferably about 10-120 ^° C.

 The reaction time is usually from several minutes to several tens of hours (for example, from 5 minutes to 50 hours).

 The compound of formula I can also be used as a salt, and examples of such salts are pharmacologically acceptable salts, such as inorganic salts (e.g., hydrochlorides, hydrobromides, sulfates, nitrates or phosphates) and organic salts (e.g., acetate, tartrates, citrates, fumarates , maleates, toluenesulfonates or methanesulfonates).

 Examples of salts of the starting material, including said compounds of formulas III and IV, are the same salts as for the compounds of formula I.

 The compound of formula I or its salt can be isolated from the reaction mixture by known isolation and purification methods, such as extraction, filtration, recrystallization, column chromatography and thin layer chromatography.

 The compound of formula I or its salt may have at least two stereoisomers. Each of these isomers or each mixture of them is included in the scope of the invention, but, if desired, each of the isomers can be synthesized separately. For example, a single isomer of a compound of formula I can be prepared from each individual isomer of a parent compound of formula II or IV. When the product is a mixture of one or more isomers, they can be separated into individual isomers by conventional methods, such as the method of producing salts of optically active acids (e.g. camphorsulfonic acid or tartaric acid) or by various types of chromatography, fractional recrystallization, etc.

 Salts of the compounds of formula I can also be prepared by a method such as treating with the indicated inorganic or organic acids a compound of formula I.

 A compound of formula I or a salt thereof having low toxicity and significant antifungal activity with a broad antifungal spectrum of action (e.g., effective against Candida, Aspergillus or Cryptococcus) can be used to prevent and treat fungal infections (e.g., candidiasis, aspergillosis or cryptococcosis) in mammals ( such as humans, pets or birds). The compound of formula I or its salt can also be used as an antifungal agent in agriculture.

 A compound of formula I or a salt thereof can be safely administered either orally or parenterally to a human in the form of pharmaceutical compositions (e.g., powder, granules, tablets or capsules), parenteral preparations (e.g., injections, topical preparations, e.g. for nose or skin, suppositories, e.g. rectal or vaginal, and so on) per se or in admixture with appropriate pharmacologically acceptable carriers, excipients or diluents.

 These drugs can be obtained by methods that are known per se and are widely used in the manufacture of pharmacological preparations.

 For example, a compound of formula I or a salt thereof according to the invention may be in the form of an injection, such as an aqueous injection comprising a dispersing agent (for example, Tween 60 [Atlas Power, USA], MCO 60 [Nikko Chemicals, Japan], carboxymethyl cellulose and sodium alginate ), a stabilizer (e.g. methylparaben, propylparaben, benzyl alcohol or chlorobutanol), an isotonic agent (e.g. sodium chloride, glycerin, sorbitol or glucose) and the like, or such as an injection obtained by dissolving, suspending or emulsifying in vegetable oil ( for example in live oil, sesame (sesame) oil, peanut oil, cottonseed oil or corn oil), propylene glycol and the like.

 In the preparation of oral preparations, the compound I or its salt according to the invention is pressed under pressure together with, for example, fibers (e.g. lactose, sugar or starch), disintegrating agents (e.g. starch or calcium carbonate), a binder (e.g. starch, arable rubber, carboxymethyl cellulose, polyvinylpyrrolidinone or hydroxypropyl cellulose), a lubricant (for example, talc, magnesium stearate or polyethylene glycol 6000) and the like or, if necessary, under a layer (according to known per se methods) of substances for taste or to give the drug properties that determine its release in the intestine. Examples are, for example, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F80, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methyl acid, Germany,; like titanium oxide and red iron oxide.

 In the case of a topical preparation, the compound of formula I or a salt thereof according to the invention can be, for example, in the form of a solid, semi-solid or liquid preparation made according to a method known per se. For example, in the case of a solid preparation, a compound of formula I or its salt is used directly or as a mixture with fillers (e.g. glucose, mannitol, starch or microcrystalline cellulose), a thickener (e.g. natural rubbers, cellulose derivatives or acrylic acid polymers) and t .d. to obtain a powder composition. In the case of a liquid preparation, the procedure is almost the same as in the case of injections to obtain an oily or aqueous suspension. In the case of a semi-solid preparation, an aqueous or oily gel or ointment is preferred. All of this can be supplemented with a pH regulating agent (e.g., carbonic acid, phosphoric acid, citric acid, hydrochloric acid or sodium hydroxide), antiseptics (e.g., p-hydroxybenzoates, chlorobutanol or benzalkonium chloride) and the like. For example, for sterilization or disinfection of the skin or mucous membrane, you can use an ointment prepared on the basis of 0.1-100 mg of the drug per 1 g of Vaseline or lanolin used as the main material.

 In the case of suppositories, the compounds according to the invention I or its salt can be prepared per se known in the form of oily or aqueous suppositories in solid, semi-solid or liquid form. Examples of oil base materials used are high fatty acid glycerides (e.g. cocoa butter, Witepsols (Dinamite-Nobell), medium fatty acids (e.g. Migriol (Dynamite-Nobell), vegetable oil (e.g. sesame oil, soybean oil or cottonseed oil ) and the like: Examples of materials used for aqueous bases are polyethylene glycol and propylene glycol, and examples of materials for aqueous gels are natural rubbers, cellulose derivatives, vinyl polymers and acrylic acid polymers.

 Doses may vary depending on the degree of infection and route of administration, in the case of adult patients (body weight 50 kg) for oral candidiasis therapy, about 0.01-100 mg / kg / day, preferably 0.1-50 mg / kg / day and more preferably 0.1-20 mg / kg / day.

 When used as an antifungal agent for crops, a compound of formula I or a salt thereof is dissolved or dispersed in a suitable liquid carrier (e.g., solvent) or mixed or adsorbed with an appropriate solid carrier (e.g., diluent or excipient) followed by, if necessary, addition emulsifier, suspending agent, lubricant, stabilizer, etc., to obtain a preparation, such as an emulsion, hydrated agent, powders, granules. Such preparations may be prepared by a known method per se. The amount of the compound of formula I or its salt used, for example in case of illness with a rice pest, is 25-150 g, preferably 40-80 g per ar of the infected rice field.

 Examples of a liquid carrier used are water, alcohols (e.g. methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol or ethylene glycol), esters (e.g. dioxane or tetrahydrofuran), aliphatic hydrocarbons (e.g. kerosene, lamp oil or black oil) aromatic hydrocarbons (e.g. benzene or toluene), halogenated hydrocarbons (e.g. methylene chloride or chloroform), acid amides (e.g. dimethylformamide or dimethylacetamide), esters (e.g. ethyl acetate or butyl acetate), nitriles (per Reamer, acetonitrile or propionitrile) and the like. They can be used both individually and as a mixture thereof in a suitable ratio.

 Examples of solid carriers are plant powder (eg, soybean powder, tobacco powder or wheat flour), mineral powder (eg, kaolin or bentonite), aluminum, sulfur powder, activated carbon, etc. They can be used individually or in the form of a mixture in a suitable ratio.

 The invention is further illustrated by the following reference examples and working examples.

¹ H-NMR spectra were measured on a Varian Gemini 200 type spectrometer (200 MHz) using tetramethylsilane as the internal standard. All δ values are given in ppm. For mixed solvents, the numbers in parentheses indicate the volume fraction of each solvent in the mixture. The designation "%" means% by weight, unless otherwise specified.

The notation in the examples has the following meanings: s: singlet, d: doublet; t: triplet; k: quadruplet; dd: doublet of doublets; m: multiplet; br: broadened; j: signal constant ¹ H-NMR: ¹ H-NMR; IR _max : IR _max ; cm ^-1 : cm ^-1 ; neat: clean.

Reference Example 1. 2 - [(1R) -1- (3,4,5,6-Tetrahydro-2H-pyran-2-yl) hydroxyethyl] -2- (2,4-difluorophenyl) oxirane (82 g, obtained according to the method described in Japanese Laid Open Application Hei 04/074168-A) and 6.3 g of pyridinium p-toluenesulfonate were dissolved in 600 ml of ethanol and the solution was stirred at 55 ^° C. for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 1 L of ethyl acetate and the resulting solution was washed with water (2 x 200 ml). The aqueous layer was extracted with ethyl acetate (2 x 100 ml). The organic layers are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane: ethyl acetate = 10: 1 to 8: 1 to 3: 1) to obtain 31.5 g (1R) -1- [2- (2,4-difluorophenyl) -2 α-oxiranyl] ethanol as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.14-1.23 (3H, m), 1.77, 2.22 (1H), 2.80, 2.92 (1H), 3.27-3 32 (1H); 4.00-4.20 (1H, m); 6.75-6.94 (2H, m); 7.36-7.48 (1H, m).

 Reference Example 2. (1R) -1- [2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol (31.5 g) and 40 g of 3,5-dinitrobenzoyl chloride are dissolved in 500 ml of methylene chloride and added while cooling with ice dropwise 24.1 ml of trimethylamine. The reaction solution was stirred at room temperature for 3.5 hours, washed with 150 ml of water and then 150 ml with 5% aqueous bicarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The crystals are separated by filtration and washed with methylene chloride. The mother liquor and wash water are combined and evaporated under reduced pressure, then 25 ml of ethyl acetate and 300 ml of methanol are added to the residue, and the mixture is cooled on ice, the crystals are separated by filtration and recrystallized from a mixture of 25 ml of ethyl acetate and 250 ml of methanol to obtain 28.7 g [(1R) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethyl] -3,5-dinitrobenzoate as colorless needles.

T.pl. 104-107 ^o C (recrystallization from ethyl acetate-hexane).

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, dd, J = 6.6 Hz, J = 1.2 Hz), 3.01 (1H, d, J = 4.6 Hz), 3 23 (1H, d, J = 4.6 Hz), 5.33 (1H, q, J = 6.6 Hz), 6.85-7.07 (2H, m), 7.54 (1H, m), 9.13 (2H, d, J = 2.2 Hz), 9.25 (1H, t, J = 2.2 Hz).

 Reference Example 3. [(1R) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethyl] - 3,5-dinitrobenzoate (50 g) was dissolved in 2 L of methanol and at room temperature 255 ml of 1N are added dropwise. sodium hydroxide solution. The reaction solution was stirred for 1 h at room temperature and neutralized with 127 ml of 1N. of hydrochloric acid. Methanol was removed under reduced pressure, then 1 L of ethyl acetate and 200 ml of water were added to the residue, and the mixture was extracted with ethyl acetate. The organic extract was washed with 200 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane: ethyl acetate = 3: 1) to obtain 25 g of (1R) -1 - [(2R) -2- (2,4-difluorophenyl) - 2-oxiranyl] ethanol as pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, dd, J = 6.6 Hz, l, 2H), 2.05 (1H, br), 2.80 (1H, d, J = 5 , 2 Hz), 3.30 (1H, d, J = 5.2 Hz), 4.01-4.17 (1H, m), 6.75-6.93 (2H, m), 7.36 -7.48 (1H, m).

 Reference Example 4. To a solution of 16.1 g of (1R) -1 - [(2R) -2- (2,4-Difluorophenyl) - 2-oxiranyl] ethanol in 320 ml of tetrahydrofuran, 63.3 g of triphenylphosphine are added under ice cooling, 29.5 g of benzoic acid and 42.0 g of diethyl azodicarboxylate and the mixture was stirred for 6 hours under argon atmosphere at room temperature. 800 ml of ethyl acetate and 500 ml of water for fractionation were added to the reaction solution, and the aqueous layer was extracted with 200 ml of ethyl acetate. The organic layers are combined and washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: hexane: ethyl acetate = 15: 1 to 7: 1) to obtain 19.2 g of [1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2 - oxiranyl] ethyl] benzoate as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, d, J = 6.6 Hz), 2.90 (1H, d, J = 5.2 Hz), 3.28 (1H, d, J = 5.2 Hz), 5.36 (1H, q, J = 6.6 Hz), 6.74-6.94 (2H, m), 7.38-7.60 (4H, m), 7.94-8.01 (2H, m).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 1725, 1615, 1600, 1505, 1450, 1425.

 [1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethyl] benzoate (15.9 g) was dissolved in 800 ml of methanol. Under ice cooling, a 28% methanol solution of sodium methylate (12.9 ml) was added and the reaction solution was stirred at room temperature for 6 hours. 63.2 ml of 1N was added to the reaction solution. hydrochloric acid and the solvent are removed by evaporation under reduced pressure.

 The residue was purified by silica gel chromatography (eluent: hexane: ethyl acetate = 6: 1 to 2: 1) to give 9.7 g (1S) -1 [(2R) -2- (2,4-difluorophenyl) -2- oxiranyl} ethanol as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, dd, J = 6.4 Hz, 2.2 Hz), 2.24 (1H, d, J = 1H), 2.92 (1H, d, J = 5 Hz), 3.28 (1H, d, J = 5 Hz), 4.12 (1H, q, J = 6.4 Hz), 6.77-6.95 (2H, m) 7.34 (1H, m).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 = 3420, 2980, 1615, 1600, 1500, 1425.

Reference Example 5. To a solution of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) - 2-oxiranyl] ethanol in 15 ml of dichloromethane was added 0.51 ml of diisopropylethylamine at -78 ^° C under nitrogen atmosphere ^. and then 0.49 ml of trifluoromethanesulfonic anhydride dropwise over 3 minutes. The mixture was stirred at -78 ^° C for 20 minutes, then at -20 ^° C for 20 minutes and concentrated to 9 ml at -10 ^° C. The concentrate was flash chromatographed on a column using silica gel (3.2 x 4 cm), eluting with dichloromethane-hexane (1: 1). The desired fraction is concentrated to 3 ml, the residue is added to a solution of 1- (4-trifluoromethylphenyl) -2 (1H, 3H) -imidazolone sodium salt obtained from 606 mg of 1- (4-trifluoromethylphenyl) -2 (1H, 3H) -imidazolone , 3 ml of dimethylformamide and 85 mg of 60% sodium hydride in oil, at -10 ^o C and stirring for 10 minutes The reaction solution was further stirred at 0 ^° C. for 20 minutes. Water (30 ml) was added to the reaction solution, and the mixture was extracted with up to 30 ml of ethyl acetate four times. The ethyl acetate extracts were washed twice with 20 ml of water and then once with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to obtain a colorless oil. It is purified by silica gel chromatography (eluent: hexane: ethyl acetate = 3: 1 to 2: 1 to 1: 1) to obtain 362 g of 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2 , 3-epoxy-1-methylpropyl] - 3- (4-trifluoromethylphenyl) -2 (1H, 3H) - imidazolone and 209 mg (2R) -2- (2,4-difluorophenyl) -2 - [(1R) - 1- [1- (4-trifluoromethylphenyl) -2-imidazolyloxy] ethyl] oxirane.

1 - [(1R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3- (4-trifluoromethylphenyl) -2 (1H, 3H) imidazolone, colorless prisms. Mp 135-136 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, d, J = 7.2 Hz), 2.72 (1H, d, J = 4.4 Hz), 2.82 (1H, d, J = 4.4 Hz), 5.09 (1H, q, J = 7.2 Hz), 6.50 (1H, d, J = 3.2 Hz), 6.64 (1H, d, J = 3.2 Hz), 6.80-6.97 (2H, m), 7.35-7.50 (1H, m), 7.69 (2H, d, J = 8.4 Hz), 7, 82 (2H, d, J = 8.4 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{kbr}}{\text{max}}$ cm ^-1 : 3010, 1684, 1616, 1523.

 Calculated,%: C 58.54; H 3.68; N, 6.83.

C ₂₀ H ₁₅ F ₅ N ₅ O ₂ .

 Found,%: C 58.80; H 3.90; N, 6.81.

 (2R) -2- (2,4-Difluorophenyl) -2 - [(1R) -1- [1- (4-trifluoromethylphenyl) - 2-imidazolyloxy] ethyl] oxirane, a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, dd, J = 6.6, 1.6 Hz), 2.89 (1H, d, J = 4.8 Hz), 3.16 ( 1H, d, J = 4.8 Hz), 5.24 (1H, q, J = 6.6 Hz), 6.70-6.91 (4H, m), 7.22-7.40 (1H , m), 7.50 (2H, d, J = 8.4 Hz), 7.70 (2H, d, J = 8.4 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3010, 1620, 1616, 1599, 1547.

SIMS (m / z): 411 (M + H) ⁺ .

 Reference Example 6. In the same manner as in Reference Example 5, starting from 423 mg of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 207 mg of 1-methyl -2 (1H, 3H) -imidazolone is prepared according to the method described in Journal of American Chemical Society, Vol. 98, p. 8218 (1976), 102 mg of 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3-methyl-2 (1H, 3H) -imidazolone a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, dd, J = 6.4, 1.4 Hz), 2.90 (1H, d, J = 5.4 Hz), 3.23 ( 1H, d, J = 5.4 Hz), 3.37 (3H, s), 5.18 (1H, d, J = 6.4 Hz), 6.48 (1H, d, J = 1.6 Hz), 6.59 (1H, J = 1.6 Hz), 6.75-6.98 (2H, m), 7.41-7.59 (1H, m).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 2980, 1734, 1616, 1600, 1539, 1506.

SIMS (m / z): 281 (M + H) ⁺ .

 Reference Example 7. By the same method as in Reference Example 5, starting from 1.95 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 1, 39 g of 1- (4-fluorophenyl) -2 (1H, 3H) -imidazolone was obtained 1.10 g of 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 -methylpropyl] -3- (4-fluorophenyl) - 2 (1H, 3H) -imidazolone and 0.88 g (2R) -2- (2,4-difluorophenyl) -2 - [(1R) -1- [1 - 4-fluorophenyl) -2-imidazolyloxy] ethyl oxirane.

 1 - [(1R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3- (4-fluorophenyl) -2 (1H, 3H) -imidazolone, colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, d, J = 7.2 Hz), 2.70 (1H, d, J = 4.8 Hz), 2.81 (1H, d, J = 4.8 Hz), 5.07 (1H, d, J = 7.2 Hz), 6.44 (1H, d, J = 3.2 Hz), 6.52 (1H, d, J = 3.2 Hz), 6.79-6.98 (2H, m), 7.02-7.20 (2H, m), 7.35-7.50 (1H, m), 7.50-7 68 (2H, m).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3130, 3050, 2985, 1736, 1693, 1618, 1600, 1512.

SIMS (M / z): 361 (M + H) ⁺ .

 (2R) -2- (2,4-Difluorophenyl) -2 - [(1R) -1- [1- (4-fluorophenyl) - 2-imidazolyloxy] ethyl] oxirane, a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, dd, J = 6.4, 1.6 Hz), 2.88 (1H, d, J = 4.8 Hz), 3.14 ( 1H, d, J = 4.8 Hz), 5.16 (1H, q, J = 6.4 Hz), 6.65-6.80 (4H, m), 7.01-7.19 (2H , m), 7.20-7.38 (3H, m).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3060, 2980, 1698, 1618, 1601, 1539, 1514, 1462.

SIMS (m / z): 361 (M + H) ⁺ .

 Reference Example 8. By the same method as in Reference Example 5, starting from 1.36 g of (1S) -1 - [(2R) -2- (2,4-Differphenyl) -2-oxiranyl] ethanol and 1.06 g of 1- (2,4-difluorophenyl) -2- (1H, 3H) -imidazolone get 0.53 g of 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy- 1-methylpropyl] -3- (2,4-difluorophenyl) - 2 (1H, 3H) -imidazolone and 0.56 g (2R) -2- (2,4-difluorophenyl) -2 - [(1R) - 1 - [1- (2,4-difluorophenyl) -2-imidazolyloxy] ethyl] oxirane.

 1- [1R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3- (2,4-difluorophenyl) -2 (1H, 3H) -imidazolone, pale yellow oil.

¹ H-NHR (CDCl ₃ ) δ: 1.38 (3H, d, J = 7.2 Hz), 2.72 (1H, d, J = 4.6 Hz), 2.83 (1H, d, J = 4.6 Hz), 5.06 (1H, q, J = 7.2 Hz), 6.44 (2H, s), 6.78-7.03 (4H, m), 7.42 ( 1H, m), 7.60 (1H, m).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 1699, 1616, 1519, 1430, 1267.

 (2R) -2- (2,4-Difluorophenyl) -2 - [(1R) -1- [1- (2,4-difluorophenyl) 2-imidazolyloxy] ethyl] oxirane, a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, d, J = 6.5 Hz), 2.87 (1H, d, J = 5 Hz), 3.13 (1H, d, J = 5 Hz), 5.4 (1H, q, J = 6.5 Hz), 6.62-7.05 (6H, m), 7.15-7.45 (2H, m).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 1705, 1616, 1549, 1520, 1462, 1435.

 Reference Example 9. By the same method as in Reference Example 5, starting from 1.35 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 963 mg 4 - (4-fluorophenyl) -3 (2H, 4H) -1,2,4-triazolone get 583 g of 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 -methyl-propyl] -4- (4-fluorophenyl) - 3 (2H, 4H) -1,2,4-triazolone in the form of colorless needles.

Mp 100-101 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d, J = 7.2 Hz), 2.88 (1H, d, J = 4.6 Hz), 3.16 (1H, d, J = 4.6 Hz), 4.94 (1H, q, J = 7.2 Hz), 6.70-6.91 (2H, m), 7.08-7.22 (2H, m), 7.25-7.51 (3H, m); 7.63 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3128, 3068, 2995, 1693, 1618, 1514, 1502, 1396.

 Calculated,%: C 59.84; H 3.91; N, 11.63.

C ₁₈ H ₁₄ F ₃ N ₃ O ₂ .

 Found,%: C 59.85; H 3.93; N, 11.74.

 Reference Example 10. By the same method as in Reference Example 5, starting from 1.66 g of (1S) -1- (2R) -2- (2,4-Difluorophenyl) -2-oxiranyl ethanol and 1.26 g 1- (methoxyphenyl) -2 (1H, 3H) -imidazolone get 1- (1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl-3- (4-methoxyphenyl) - 2 (1H, 3H) -imidazolone 617 mg as colorless prisms.

Mp 150-151 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 7.2 Hz), 2.70 (1H, d, J = 4.8 Hz), 2.81 (1H, d, J = 4.8 Hz), 3.82 (3H, s), 5.07 (1H, q, J = 7.2 Hz), 6.41 (1H, d, J = 3 Hz), 6.49 (1H, d, J = 3Hz), 6.78-6.95 (2H, m), 6.94 (2H, d, J = 9 Hz), 7.35-7.50 (1H, m), 7.49 (2H, d, J = 9 Hz).

 Calculated,%: C 64.51; H 4.87; N, 7.52.

C ₂₀ H ₁₈ F ₂ N ₂ O ₃ .

 Found,%: C 64.26; H 4.97; N, 7.46.

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3250, 3010, 1693, 1620, 1514, 1504, 1441.

 Reference Example 11

 In the same manner as in Reference Example 5, starting from 1.73 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 1.32 g of 4- ( 4-methoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methyl-propyl ] -4- (4-methoxyphenyl) - 3 (2H, 4H) -1,2,4-triazolone 869 mg as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7 Hz), 2.88 (1H, d, J = 4.6 Hz), 3.16 (1H, d, J = 4.6 Hz), 3.83 (3H, s), 4.95 (1H, q, J = 7 H), 6.74-6.90 (2H, m), 6.96 (2H, d, J = 9.2 Hz), 7.28-7.42 (1H, m), 7.36 (2H, d, J = 9.2 Hz), 7.59 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3100, 3005, 2920, 1699, 1616, 1601, 1556, 1519.

SIMS (m / z): 374 (M + H) ⁺ .

 Reference Example 12. By the same method as in Reference Example 5, starting from 1.36 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 1.32 g of 1- (4-trifluoromethoxyphenyl) -2 (1H, 3H) -imidazolone get 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methyl-propyl] - 3- (4-trifluoromethoxyphenyl) -2 (1H, 3H) -imidazolone (0.60 g) and 0.46 g (2R) -2- (2,4-difluorophenyl) -2 - [(1R) -1- [1- (4-trifluoromethoxyphenyl) -2-imidazolyloxy] ethyl] oxirane.

 1 - [(1R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3- (4-trifluoromethoxyphenyl) -2 (1H, 3H) -imidazolone - colorless crystals.

Mp 99-100 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, d, J = 7.2 Hz), 2.71 (1H, d, J = 4.8 Hz), 2.80 (1H, d, J = 4.8 Hz), 5.07 (1H, q, J = 7.2 Hz), 6.46 (1H, d, J = 3.2 Hz), 6.56 (1H, d, J = 3.2 Hz), 6.80-6.96 (2H, m), 7.28 (2H, d, J = 9 Hz), 7.40 (1H, m), 7.67 (2H, d, J = 9 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 1682, 1620, 1606, 1516, 1433, 1353.

 (2R) -2- (2,4-Difluorophenyl) -2 - [(1R) -1- [1- (4-trifluoromethoxyphenyl) - 2-imidazolyloxy] ethyl] oxirane is a pale yellow oil.

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 1616, 1558, 1541, 1516, 1458, 1261.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, dd, J = 6.6 Hz, J = 1.6 Hz), 2.90 (1H, d, J = 5 Hz), 3.14 (1H, d, J = 5 Hz), 5.19 (1H, q, J = 6.6 Hz), 6.70-6.90 (4H, m), 7.18-7.50 (5H, m).

 Reference Example 13. By the same method as in Reference Example 5, starting from 1.64 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 1.87 g 4- (trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl ] - 4- (4-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone (1.26 g) as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (3H, d, J = 7.4 Hz), 2.89 (1H, d, J = 4.6 Hz), 3.16 (1H, d, J = 4.6 Hz), 4.95 (1H, q, J = 7.2 Hz), 6.74-6.90 (2H, m), 7.28-7.42 (1H, m), 7.64-7.86 (5H, m).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 1700, 1620, 1390, 1320, 1110.

 Calculated,%: C 55.48; H 3.43; N, 10.22.

C ₁₉ H ₁₄ F ₅ N ₃ O ₂ .

 Found,%: C 55.56; H 3.43; N, 10.15.

 Reference Example 14. By the same method as in Reference Example 5, starting from 2.49 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 2.52 g 2- (4-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone get 4 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 methylpropyl] - 2- (4-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone (1.13 g) and 618 mg (2R) -2- (2,4-difluorophenyl) -2 - [(1R) -1- [1- (4-trifluoromethylphenyl) -1H-1,2,4-triazol-5-yloxy] ethyl] oxirane.

 4- [1R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] - 2- (4-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4- triazolone, colorless prisms.

Mp 164-165 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 7.2 Hz), 2.74 (1H, d, J = 4.2 Hz), 2.78 (1H, d, J = 4.2 Hz), 5.02 (1H, q, J = 7.2 Hz), 6.80-7.01 (2H, m), 7.35-7.51 (1H, m), 7.64 (1H, s), 7.70 (2H, d, J = 8.8 Hz), 8.18 (2H, d, J = 8.8 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3060, 1722, 1619, 1601, 1564, 1524.

 Calculated,%: C 55.48; H 3.43; N, 10.22.

C ₁₉ H ₁₄ F ₅ N ₃ O ₂ .

 Found,%: C 55.17; H 3.39; N, 10.19.

 (2R) -2- (2,4-Difluorophenyl) -2 - [(1R) -1- [1- (4-trifluoromethylphenyl) -1H- 1,2,4-triazol-5-yloxy] ethyl] oxirane, colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.53 (3H, dd, J = 6.6, 1.6 Hz), 2.94 (1H, d, J = 4.8 Hz), 3.22 ( 1H, d, J = 4.8 Hz), 5.37 (1H, q, J = 6.6 Hz), 6.75-6.98 (2H, m), 7.38-7.52 (1H , m), 7.69 (1H, s), 7.70 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3050, 1618, 1599, 1558, 1540.

Reference Example 15. By the same method as in Reference Example 5, starting from 1.36 g of (1S) -1 - [(2R) -2- (2,4-Differphenyl) -2-oxiranyl] ethanol and 1.33 g 4- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 methylpropyl] - 4- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone (1.45 g) as colorless prisms. Mp 103-106 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (3H, d, J = 7 Hz), 2.88 (1H, d, J = 4.8 Hz), 3.16 (1H, d, J = 4.8 Hz), 4.94 (1H, q, J = 7 Hz), 6.72-6.92 (2H, m), 7.25-7.45 (3H, m), 7.56 ( 2H, d, J = 9.2 Hz), 7.66 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3136, 3082, 1697, 1620, 1562, 1514, 1430, 1392, 1257, 1222.

 Reference Example 16. The same method as in Reference Example 5, starting from 0.83 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 0.83 g of 1- (4-isopropylphenyl) -2 (1H, 3H) -imidazolone get 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3- (4-Isopropylphenyl) -2 (1H, 3H) -imidazolone (0.25 g) and 0.22 g (2R) -2- (2,4-difluorophenyl) -2 - [(1R) -1- [1 - (4-isopropylphenyl) - 2-imidazolyloxy] ethyl] oxirane.

1 - [(1R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3- (4-isopropylphenyl) -2 (1H, 3H) -imidazolone, colorless crystals. Mp 119-120 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7.0 Hz), 1.36 (3H, d, J = 7.4 Hz), 2.70 (1H, d, J = 5 Hz), 2.81 (1H, d, J = 5 Hz), 2.92 (1H, quintet, J = 7.0 Hz), 5.08 (1H, q, J = 7.4 Hz ), 6.42 (1H, d, J = 3.2 Hz), 6.54 (1H, d, J = 3.2 Hz), 6.80-6.93 (2H, m), 7.27 (2H, d, J = 8.6 Hz), 7.35-7.48 (1H, m), 7.52 (2H, d, J = 8.6 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 2950, 1680, 1515, 1495, 1420.

 (2R) -2- (2,4-Difluorophenyl) -2 - [(1R) -1- [1- (4-isopropylphenyl) - 2-imidazolyloxy] ethyl] oxirane, a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 7 Hz), 1.43 (3H, d, J = 6.6 Hz), 2.88 (1H, d, J = 5.0 Hz), 2.97 (1H, q, J = 7.0 Hz), 3.15 (1H, d, J = 5.0 Hz), 5.14 (1H, d, J = 6, 6 Hz), 6.67-6.82 (4H, m), 7.26 (4H, s), 7.22-7.35 (1H, m).

 Reference Example 17. By the same method as in Reference Example 5, starting from 1.36 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 1.07 g 4- (2,4-difluorophenyl) -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy -1-methylpropyl] -4- (2,4-difluorophenyl) - 3 (2H, 4H) -1,2,4-triazolone (1.20 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (3H, d, J = 7.2 Hz), 2.89 (1H, d, J = 4.6 Hz), 3.18 (1H, d, J = 4.6 Hz), 4.94 (1H, q, J = 7.2 Hz), 6.76-6.94 (2H, m), 6.95-7.10 (2H, m), 7.28-7.42 (1H, m), 7.50-7.65 (1H, m), 7.58 (1H, d, J = 2.2 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 1716, 1616, 1558, 1519, 1427, 1403, 1270.

 Reference Example 18. By the same method as in Reference Example 5, starting from 2.27 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 1.80 g 2- (4-fluorophenyl) -3 (2H, 4H) -1,2,4-triazolone get 4 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 -methylpropyl] -2- (4-fluorophenyl) - 3 (2H, 4H) -1,2,4-triazolone (848 mg) and 446 mg (2R) -2- (2,4-difluorophenyl) -2- [ 1R) -1- [1- (4-fluorophenyl) -1H-1,2,4-triazol-5-yloxy] ethyl] oxirane.

4 - [(1R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] - 2- (4-fluorophenyl) -3 (2H, 4H) -1,2,4 Triazolone, colorless prisms. Mp 163-164 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, d, J = 7.2 Hz), 2.73 (1H, d, J = 4.2 Hz), 2.77 (1H, d, J = 4.2 Hz), 5.01 (1H, q, J = 7.2 Hz), 6.82-7.01 (2H, m), 7.12 (2H, t, J = 8.8 Hz), 7.35-7.50 (1H, m), 7.60 (1H, s), 7.96 (2H, dd, J = 8.8, 4.6 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3060, 1714, 1620, 1603, 1562, 1512.

 Calculated,%: C 59.84; H 3.91; N, 11.63.

C ₁₈ H ₁₄ F ₃ N ₃ O ₂ .

 Found,%: C 59.51; H 3.83; N, 11.83.

 (2R) -2- (2,4-Difluorophenyl) -2 - [(1R) -1- [1- (4-fluorophenyl) -1H-1,2,4-triazol-5-yloxy] ethyl] oxirane, colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.50 (3H, dd, J = 6.6, 1.6 Hz), 2.93 (1H, d, J = 4.8 Hz), 3.20 ( 1H, d, J = 4.8 Hz), 5.27 (1H, q, J = 6.6 Hz), 6.76-6.98 (2H, m), 7.13 (2H, t, J = 8.2 Hz), 7.30-7.49 (1H, m), 7.63 (2H, dd, J = 4.6, 8.2 Hz), 7.64 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3077, 2995, 1618, 1601, 1543.

 Reference Example 19. By the same method as in Reference Example 5, based on 681 mg of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.0 g 4 - [4- (4-benzyl-1-piperazinyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl) - 2,3-epoxy-1-methylpropyl] - 4- [4- (4-benzyl-1-piperazinyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone (293 mg) as a colorless powder .

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, d, J = 7 Hz), 2.61 (4H, t, J = 4.8 Hz), 2.87 (1H, d, J = 4.8 Hz), 3.16 (1H, d, J = 4.8 Hz), 3.22 (4H, t, J = 4.8 Hz), 3.57 (2H, s), 4.96 (1H, q, J = 7 Hz), 6.72-6.91 (2H, m), 6.94 (2H, d, J = 9 Hz), 7.21-7.45 (8H, m) 7.57 (1H, s).

 Reference Example 20. By the same method as in Reference Example 5, starting from 1.72 g (1S) -1-1 (2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 1.68 g of 4- (4-isopropylphenyl) -3 (2H, 4H) -1,2,4-triazolone get a mixture of the order of 1: 1 (0.89 g) 2 - [(1R, 2S) -2- (2,4 -difluorophenyl) -2,3-epoxy-1-methylpropyl] -4- (4-isopropylphenyl) -3 (2H, 4H) -1,2,4-triazolone and (1R) -1 - [(2R) -2 - (2,4-difluorophenyl) -2-oxiranyl] ethanol.

¹ H-NMR (CDCl ₃ ) δ: 1.16 (dd, J = 6.6, 1.0 Hz), 1.25 (d, J = 6.8 Hz), 1.46 (d, J = 7 Hz), 1.78 (d, J = 8 Hz), 2.79 (d, J = 5 Hz), 2.88 (d, J = 5 Hz), 2.94 (q, J = 6, 8 Hz), 3.16 (d, J = 5 Hz), 3.30 (d, J = 5 Hz), 4.02-4.17 (m), 4.96 (q, J = 7 Hz) , 6.73-6.92 (m), 7.27-7.45 (m), 7.62 (s).

 Reference Example 21. By the same method as in Reference Example 5, starting from 1.41 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.30 g of 1- (4-trifluoromethylphenyl) -5 (1H, 4H) -tetrazolone get 1- [1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] - 4- ( 4-trifluoromethylphenyl) -5 (1H, 4H) -tetrazolone (1.38 g) and 0.168 g (2R) -2- (2,4-difluorophenyl) -2 - [(1R) - 1- [1- (4 trifluoromethylphenyl) -1H-tetrazol-5-yloxy] ethyl] oxirane.

 1 - [(1R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] - 4- (4-trifluoromethylphenyl) -5 (1H, 4H) -tetrazolone, a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.61 (3H, d, J = 7.2 Hz), 2.93 (1H, d, J = 4.6 Hz), 3.16 (1H, d, J = 4.6 Hz), 4.97 (1H, q, J = 7.2 Hz), 6.72-6.94 (2H, m), 7.23-7.40 (1H, m), 7.75 (2H, d, J = 8.4 Hz); 8.13 (2H, d, J = 8.4 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3100, 1734, 1618, 1522, 1508, 1429.

SIMS (m / z): 413 (M + H) ⁺ .

 (2R) -2- (2,4-Differphenyl) -2 - [(1R) -1- [1- (4-trifluoromethylphenyl) - 1H-tetrazol-5-yloxy] ethyl] oxirane, colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.59 (3H, dd, J = 6.6, 1.6 Hz), 2.98 (1H, d, J = 4.6 Hz), 3.23 ( 1H, d, J = 4.6 Hz), 5.39 (1H, q, J = 6.6 Hz), 6.75-6.98 (2H, m), 7.32-7.49 (1H , m), 7.80 (2H, d, J = 9 Hz), 7.82 (2H, d, J = 9 Hz).

SIMS (m / z): 413 (M + H) ⁺ .

 Reference Example 22. By the same method as in Reference Example 5, from 0.50 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 0.72 g of 1- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone get 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2, 3-epoxy-1-methylpropyl] - 3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2- (1H, 3H) -imidazolone (0.21 g) and 0.14 g (2R ) -2- (2,4-difluorophenyl) -2 - [(1R) -1-1- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2-imidazolyloxy] ethyl] oxirane.

 1 - [(1R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 7.2 Hz), 2.70 (1H, d, J = 4.7 Hz), 2.81 (1H, d, J = 4.7 Hz), 4.36 (2H, t, J = 12 Hz), 5.07 (1H, q, J = 7.2 Hz), 6.06 (1H, tt, J = 4, 8, 53 Hz), 6.43 (1H, d, J = 3 Hz), 6.51 (1H, d, J = 3 Hz), 6.79-7.02 (4H, m), 7.26 -7.47 (1H, m); 7.52-7.60 (2H, m).

 (2R) -2- (2,4-Difluorophenyl) -2 - [(1R) -1- [1-4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2-imidazolyloxy] ethyl oxiran.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, d, J = 6.6 Hz), 2.86 (1H, d, J = 5.2 Hz), 3.14 (1H, d, J = 5.2 Hz), 4.32-4.47 (2H, m), 5.19 (1H, q, J = 6.6 Hz), 6.09 (1H, tt, J = 4.8 , 53 Hz), 6.72-6.83 (4H, m), 6.90-7.02 (2H, m), 7.24-7.47 (3H, m).

Reference Example 23. By the same method as in Reference Example 5, starting from 543 mg of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 809 mg of 4- [ 4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3 (2H, 4H) -1,2,4-triazolone, prepared according to the method described in Journal of Medicinal Chemistry, vol. 27, p. 894 (1984), 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -4- [4- [4- (4-methoxyphenyl) - 1-piperazinyl] phenyl] -3 (2H, 4H) - 1,2,4-triazolone (373 mg) as colorless prisms. Mp 175-176 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7.2 Hz), 2.88 (1H, d, J = 4.8 Hz), 3.16 (1H, d, J = 4.8 Hz), 3.17-3.30 (8H, m), 3.79 (3H, s), 4.96 (1H, q, J = 7.2 Hz), 6.73- 6.96 (2H, m), 6.87 (2H, d, J = 9.2 Hz), 6.96 (2H, d, J = 9.2 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.34 (2H, d, J = 8.8 Hz), 7.24-7.41 (1H, m), 7.58 (1H, s).

 Calculated,%: C 65.28; H 5.48; N, 13.13.

C ₂₉ H ₂₉ F ₂ N ₅ O ₃ .

 Found,%: C 65.30; H 5.50; N 13.03.

 Reference Example 24. By the same method as in Reference Example 5, starting from 1.2 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 1.1 g 4- (3-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 -methylpropyl] - 4- (3-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone (0.85 g) as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d, J = 7 Hz), 2.89 (1H, d, J = 4.6 Hz), 3.16 (1H, d, J = 4.6 Hz), 4.95 (1H, q, J = 7Hz), 6.75-6.90 (3H, m), 7.28-7.45 (2H, m), 7.73 (1H , s), 7.71-7.82 (2H, m).

 Reference Example 25. By the same method as in Reference Example 5, starting from 1.43 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.03 g of 1- (4-fluorophenyl) -5 (1H, 4H) -tetrazolone get 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -4- (4-fluorophenyl) - 5 (1H, 4H) -tetrazolone (1.22 g) and 205 g (2R) -2- (2,4-difluorophenyl) -2 - [(1R) - 1- [1- ( 4-fluorophenyl) -1H-tetrazol-5-yloxy] ethyl] oxirane.

 1- (1R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl- 4- (4-fluorophenyl) -5 (1H, 4H) -tetrazolone, colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.60 (3H, d, J = 7.2 Hz), 2.93 (1H, d, J = 4.4 Hz), 3.17 (1H, d, J = 4.4 Hz), 4.93 (1H, q, J = 7.2 Hz), 6.75-6.92 (2H, m), 7.10-7.40 (3H, m), 7.82-7.99 (2H, m).

SIMS (m / z): 363 (M + H) ⁺ .

 (2R) -2- (2,4-Difluorophenyl) -2 - [(1R) -1- [1- (4-fluorophenyl) -1H-tetrazol-5-yloxy] ethyl] oxirane, colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.56 (3H, dd, J = 6.6, 1.6 Hz), 2.96 (1H, d, J = 4.6 Hz), 3.20 ( 1H, d, J = 4.6 Hz), 5.31 (1H, q, J = 6.6 Hz), 6.74-6.96 (2H, m), 7.23 (2H, t, J = 9 Hz), 7.30-7.49 (1H, m), 7.65 (2H, dd, J = 4.6 Hz).

SIMS (m / z): 363 (M + H) ⁺ .

Reference Example 26. By the same method as in Reference Example 5, starting from 1.42 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.92 g 4- (4-pyridyl) -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 methylpropyl] -4- (4-pyridyl) - 3 (2H, 4H) -1,2,4-triazolone (0.66 g) as colorless prisms. T. pl. 96-97 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d, J = 7 Hz), 2.88 (1H, d, J = 4.6 Hz), 3.15 (1H, d, J = 4.6 Hz), 4.93 (1H, q, J = 7 Hz), 6.72-6.91 (2H, m), 7.26-7.40 (1H, m), 7.62 ( 2H, dd, J = 4.8, 1.6 Hz), 7.83 (1H, s), 8.70 (2H, dd, J = 4.8, 1.6 Hz).

 Calculated,%: C 59.30; H 4.10; N, 16.27.

C ₁₇ H ₁₄ F ₂ N ₄ O ₂ .

 Found,%: C 59.23; H 4.12; N, 16.36.

 Reference Example 27. By the same method as in Reference Example 5, starting from 536 mg (1S) -1- (2R) -2- (2,4-difluorophenyl) -2-oxiranyl ethanol and 305 mg 4- (4- pyrimidinyl) -3 (2H, 4H) -1,2,4-triazolone get 2- (1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl-4- (4 -pyrimidinyl) - 3 (2H, 4H) -1,2,4-triazolone (199 mg) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d, J = 7.2 Hz), 2.90 (1H, d, J = 4.6 Hz), 3.16 (1H, d, J = 4.6 Hz), 4.90 (1H, q, J = 7.2 Hz), 6.72-6.90 (2H, m), 7.25-7.40 (1H, m), 8.34 (1H, dd, J = 5.6, 1.2 Hz), 8.46 (1H, s), 8.80 (1H, d, J = 5.6 Hz), 9.03 (1H , d, J = 1.2 Hz).

SIMS (m / z): 346 (M + H) ⁺ .

 Reference Example 28. By the same method as in Basic Example 5, starting from 1.36 g of (1S) -1- (2R) -2- (2,4-Difluorophenyl) -2-oxiranyl ethanol and 0.91 g 4 - (2,2,2-trifluoroethyl) -3 (2H, 4H) -1,2,4-triazolone get 2- (1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy- 1-methylpropyl- 4- (2,2,2-trifluoroethyl) -3 (2H, 4H) -1,2,4-triazolone (1.25 g) as a colorless oil.

IRυ cm ^-1 (film): 1716, 1704, 1652, 1616, 1558, 1508.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, d, J = 7 Hz), 2.86 (1H, d, J = 4.6 Hz), 3.11 (1H, d, J = 4.6 Hz), 4.05-4.35 (2H, m), 4.87 (1H, q, J = 7 Hz), 6.70-6.90 (2H, m), 7.20- 7.25 (1H, s), 7.46 (1H, s).

 Reference Example 29. By the same method as in Reference Example 5, starting from 1.0 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.16 g 4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4 -difluorophenyl) -2,3-epoxy-1-methylpropyl] - 4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (1 , 34 g) as a colorless oil.

IRυ cm ^-1 (film): 1716, 1705, 1616, 1558, 1516, 1257, 1108.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d, J = 7 Hz), 2.88 (1H, d, J = 4.8 Hz), 3.16 (1H, d, J = 4.8 Hz), 4.38 (2H, t, J = 11.8 Hz), 4.94 (1H, q, J = 7 Hz), 6.07 (1H, tt, J = 53 Hz, J = 4.8 Hz), 6.75-6.90 (2H, m), 6.95-7.12 (2H, m), 7.28-7.55 (3H, m), 7.63 ( 1H, s).

 Reference Example 30. By the same method as in Reference Example 5, based on 1.0 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.1 g 4- (2-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 -methylpropyl] - 4- (2-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone (0.4 g) as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (3H, d, J = 7.2 Hz), 2.91 (1H, d, J = 4.4 Hz), 3.19 (1H, d, J = 4.4 Hz), 4.97 (1H, q, J = 7.2 Hz), 6.75-6.90 (2H, m), 7.29-7.45 (3H, m), 7.56-7.84 (3H, m).

 Reference Example 31. By the same method as in Reference Example 5, starting from 1.43 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.94 g 4- (4-isopropoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 methylpropyl] - 4- (4-isopropoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone (0.84 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J = 6.2 Hz), 1.46 (3H, d, J = 7.2 Hz), 2.88 (1H, d, J = 4.6 Hz), 3.17 (1H, d, J = 4.6 Hz), 4.56 (1H, septet, J = 6.2 Hz), 4.96 (1H, q, J = 7.2 Hz), 6.72-6.91 (2H, m), 6.94 (2H, d, J = 8.4 Hz), 7.28-7.40 (1H, m), 7, 34 (2H, d, J = 8.4 Hz), 7.58 (1H, s).

SIMS (m / z): 402 (M + H) ⁺ .

 Reference Example 32. By the same method as in Reference Example 5, starting from 1.38 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.21 g 4- (3-methylbutyl) -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 -methylpropyl] -4- (3-methylbutyl) - 3 (2H, 4H) -1,2,4-triazolone (1.15 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.94 (6H, dd, J = 6.2, 1.8 Hz), 1.41 (3H, d, J = 7.2 Hz), 1.40- 1.70 (3H, m), 2.85 (1H, d, J = 4.6 Hz), 3.10 (1H, d, J = 4.6 Hz), 3.59 (2H, t, J = 6.2 Hz), 4.91 (1H, q, J = 7.2 Hz), 6.67-6.79 (2H, m), 7.33 (1H, s), 7.72-7 39 (1H, m).

SIMS (m / z): 338 (M + H) ⁺ .

 Reference Example 33. By the same method as in Reference Example 5, starting from 1.0 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.11 g 4- [4- (1,1,2,2-tetrafluoroethoxy] -3 (2H, 4H) -1,2,4-triazolone get 2 - [(1R, 2S) -2- (2,4-difluorophenyl ) -2,3-epoxy-1-methylpropyl] - 4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (0.99 g) in the form of a colorless oil.

IRυ cm ^-1 (film): 1699, 1619, 1600, 1554, 1510, 1400.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d, J = 7.2 Hz), 2.89 (1H, d, J = 4.6 Hz), 3.16 (1H, d, J = 4.6 Hz), 4.95 (1H, q, J = 7.2 Hz), 5.93 (1H, tt, J = 53 Hz, J = 2.8 Hz), 6.74-6 , 90 (2H, m), 7.25-7.45 (3H, m), 7.55 (2H, dt, J = 9 Hz, J = 2.2 Hz), 7.67 (1H, s) .

 Reference Example 34. By the same method as in Reference Example 5, starting from 1.34 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.15 g 2- (4-chlorophenyl) -3 (2H, 4H) -1,2,4-triazolone get 2- (4-chlorophenyl) -4 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3 (2H, 4H) -1,2,4-triazolone (519 mg) and 424 mg (2R) -2 - [(1R) -1- [1- ( 4-chlorophenyl) -1H-1,2,4-triazol-5-yloxy] ethyl] -2- (2,4-difluorophenyl) oxirane.

2- (4-Chlorophenyl) -4 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3 (2H, 4H) -1,2,4 Triazolone, colorless prisms. Mp 172-173 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, d, J = 7.4 Hz), 2.73 (1H, d, J = 4.4 Hz), 2.77 (1H, d, J = 4.4 Hz), 5.00 (1H, q, J = 7.4 Hz), 6.81-6.99 (2H, m), 7.32-7.48 (1H, m), 7.39 (2H, d, J = 9 Hz), 7.60 (1H, s), 7.96 (2H, d, J = 9 Hz).

 Calculated,%: C 55.90; H 3.91; N, 10.86.

C ₁₈ H ₁₄ ClF ₂ N ₃ O ₂ • 0.5H ₂ O.

 Found,%: C 56.20; H 3.69; N, 10.93.

 (2R) -2 - [(1R) -1- [1- (4-Chlorophenyl) -1H-1,2,4-triazol-5-yloxy] ethyl] - 2- (2,4-difluorophenyl) oxirane, in the form of a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.51 (3H, dd, J = 6.6, 1.6 Hz), 2.93 (1H, d, J = 4.6 Hz), 3.20 ( 1H, d, J = 4.6 Hz), 5.30 (1H, q, J = 6.6 Hz), 6.78-6.96 (2H, m), 7.31-7.46 (1H , m), 7.40 (2H, d, J = 9 Hz), 7.62 (2H, d, J = 9 Hz), 7.64 (1H, s).

SIMS (m / z): 378 (M + H) ⁺ .

 Reference Example 35. In the same manner as in Reference Example 5, starting from 1.53 g of (1S) -1 - [(2R) -2- (2,4-diferephenyl) -2-oxiranyl] ethanol and 1.50 g 2- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone get 4 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 -methylpropyl] - 2- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone (829 mg) and 778 mg (2R) -2- (2,4-difluorophenyl) -2- [ (1R) -1- [1- (4-trifluoromethoxyphenyl) -1H-1,2,4-triazol-5-yloxy] ethyl] oxirane.

4 - [(R, 2S) -2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] - 2- (4-trifluoromethoxyphenyl) -3 (2H, 4 H) -1.2, 4-triazolone, colorless prisms. Mp 116-117 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, d, J = 7.2 Hz), 2.74 (1H, d, J = 4 Hz), 2.77 (1H, d, J = 4 Hz), 5.01 (1H, q, J = 7.2 Hz), 6.80-7.00 (2H, m), 7.28 (2H, d, J = 9.2 Hz), 7 , 33-7.50 (1H, m), 7.61 (1H, s), 8.05 (2H, d, J = 9.2 Hz).

 Calculated,%: C 53.40; H 3.30; N, 9.83.

C ₁₉ H ₁₄ F ₅ N ₃ O ₃ .

 Found,%: C 53.09; H 3.23; N, 9.83.

 (2R) -2- (2,4-Difluorophenyl) -2 - [(1R) -1- [1- (4-trifluoromethoxyphenyl) -1H- 1,2,4-triazol-5-yloxy] ethyl] oxirane, colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.51 (3H, d, J = 6.6 Hz), 2.94 (1H, d, J = 4.8 Hz), 3.20 (1H, d, J = 4.8 Hz), 5.31 (1H, q, J = 6.6 Hz), 6.78-6.98 (2H, m), 7.29 (2H, d, J = 9 Hz) 7.35-7.50 (1H, m); 7.65 (1H, s); 7.71 (2H, d, 9 Hz).

SIMS (m / z): 428 (M + H) ⁺ .

 Reference Example 36. By the same method as in Reference Example 5, starting from 1.54 g of (1S) -1 - [(2R) - (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.52 g of 1 - (4-trifluoromethoxyphenyl) -5 (1H, 4H) -tetrazolone get 1.76 g of 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] - 4- (4-trifluoromethoxyphenyl) -5 (1H, 4H) -tetrazolone as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.60 (3H, d, J = 7.4 Hz), 2.93 (1H, d, J = 4.4 Hz), 3.17 (1H, d, J = 4.4 Hz), 4.93 (1H, q, J = 7.4 Hz) 6.75-6.96 (2H, m), 7.24-7.43 (1H, m), 7 35 (2H, d, J = 9.2 Hz), 8.00 (2H, d, J = 9.2 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 2980, 1732, 1620, 1601, 1514, 1427.

SIMS (m / z): 429 (M + H) ⁺ .

 Reference Example 37. By the same method as in Reference Example 5, starting from 1.39 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.63 g of 1- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -5 (1H, 4H) -tetrazolone get 1.27 g of 1 - [(1R, 2S) -2- (2,4-difluorophenyl ) -2,3-epoxy-1-methylpropyl] - 4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -5 (1H, 4H) -tetrazolone as a colorless oil.

¹ H-MMR (CDCl ₃ ) δ: 1.60 (3H, d, J = 7.2 Hz), 2.93 (1H, d, J = 4.4 Hz), 3.17 (1H, d, J = 4.4 Hz), 4.40 (2H, t, J = 11.8 Hz), 4.93 (1H, q, J = 7.2 Hz), 6.08 (1H, tt, J = 53.2, 4.6 Hz), 6.73-6.94 (2H, m), 7.05 (2H, d, J = 9 Hz), 7.23-7.41 (1H, m), 7.86 (2H, d, J = 9 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3000, 1745, 1622, 1601, 1522, 1431.

SIMS (m / z): 475 (M + H) ⁺ .

 Reference Example 38. By the same method as in Reference Example 5, starting from 1.38 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.09 g of 1- (4-chlorophenyl) -5 (1H, 4H) -tetrazolone get 1.27 g of 1- (4-chlorophenyl) -4 - [(1R, 2S) -2- (2,4-diferephenyl) -2 , 3-epoxy-1-methylpropyl] - 5 (1H, 4H) -tetrazolone as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.60 (3H, d, J = 7.2 Hz), 2.92 (1H, d, J = 4.4 Hz), 3.16 (1H, d, J = 4.4 Hz), 4.92 (1H, q, J = 7.2 Hz), 6.75-6.96 (2H, m), 7.25-7.41 (1H, m), 7.45 (2H, d, J = 9 Hz); 7.90 (2H, d, J = 9 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3018, 1732, 1620, 1506, 1425.

SIMS (m / z): 379 (M + H) ⁺ .

Reference Example 39. By the same method as in Reference Example 5, based on 1.01 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.15 g of 1- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2 (1H, 3H) -imidazole 0.36 g of 1 - [(1R, 2S) -2- (2,4-difluorophenyl ) -2,3-epoxy-1-methylpropyl] - 3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2 (1H, 3H) -imidazolone in the form of colorless needles. Mp 117-118 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, d, J = 7.2 Hz), 2.71 (1H, d, J = 5 Hz), 2.81 (1H, d, J = 5 Hz), 5.08 (1H, q, 7.2 Hz), 5.93 (1H, tt, J = 53, 2.8 Hz), 6.46 (1H, d, J = 3 Hz), 6.57 (1H, d, J = 3 Hz), 6.80-6.95 (2H, m), 7.28 (2H, d, J = 9Hz), 7.36-7.48 (1H, m), 7.67 (2H, d, J = 9 Hz).

 Reference Example 40. By the same method as in Reference Example 5, starting from 0.80 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.78 g of 1- (4-chlorophenyl) -2 (1H, 3H) -imidazolone get 0.18 g of 1- (4-chlorophenyl) -3 - [(1R, 2S) -2- (2,4-difluorophenyl) -2 , 3-epoxy-1-methylpropyl] - 2 (1H, 3H) -imidazole in the form of a colorless viscous oil.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 7 Hz), 2.70 (1H, d, J = 5 Hz), 2.80 (1H, d, J = 5 Hz ), 5.07 (1H, q, J = 7 Hz), 6.45 (1H, d, J = 3.2 Hz), 6.55 (1H, d, J = 3.2 Hz), 6, 79-6.94 (2H, m), 7.34-7.46 (1H, m), 7.38 (2H, d, J = 9 Hz), 7.59 (2H, d, J = 9 Hz )

 Reference Example 41. By the same method as in Reference Example 5, based on 0.66 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 0.65 g of 4- (4-chlorophenyl) -3- (2H, 4H) -1,2,4-triazolone get 0.23 g of 4- (4-chlorophenyl) -2 - [(1R, 2S) -2- (2 , 4-difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3 (2H, 4H) -1,2,4-triazolone as a colorless viscous oil.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7 Hz), 2.88 (1H, d, J = 5 Hz), 3.15 (1H, d, J = 5 Hz ), 4.94 (1H, q, J = 7 Hz), 6.76-6.88 (2H, m), 7.26-7.50 (1H, m), 7.46 (4H, s) 7.66 (1H, s).

 Reference Example 42. By the same method as in Reference Example 5, based on 0.83 g of (1S) -1-1 (2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.56 g 1- [4- (2,2,3,3,4,4,5,5-octafluoropentoxy) phenyl] -2- (1H, 3H) -imidazolone get 0.30 g 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3- [4- (2,2,3,3,4,4,5,5-octafluoropentoxy) phenyl] -2 (1H, 3H) -imidazolone as a colorless viscous oil.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 7.2 Hz), 2.70 (1H, d, J = 4.8 Hz), 2.80 (1H, d, J = 4.8 Hz), 4.48 (2H, t, J = 13 Hz), 5.07 (1H, q, J = 7.2 Hz), 6.09 (1H, tt, J = 52, 5.6 Hz), 6.43 (1H, d, J = 3.2 Hz), 6.51 (1H, d, J = 3.2 Hz), 6.79-6.96 (2H, m) 7.00 (2H, d, J = 9 Hz), 7.34-7.47 (1H, m), 7.57 (2H, d, J = 9 Hz).

 Reference Example 43. By the same method as in Reference Example 5, starting from 0.68 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 0.70 g of 1- [4- (2,2,2-trifluoroethoxy) phenyl] -2 (1H, 3H) -imidazolone, 0.30 g of 1 - [(1R, 2S) -2- (2,4-difluorophenyl) - 2,3-epoxy-1-methylpropyl] - 3- [4- (2,2,2-trifluoroethoxy) phenyl] -2 (1H, 3H) -imidazolone as colorless prisms.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 7.2 Hz), 2.71 (1H, d, J = 4.8 Hz), 2.81 (1H, d, J = 4.8 Hz), 4.37 (2H, q, J = 8 Hz), *) 6.52 (1H, d, J = 3.2 Hz), 6.43 (1H, q, J = 3.2 Hz), 6.80-6.95 (2H, m), 7.00 (2H, d, J = 9.2 Hz), 7.35-7.48 (1H, m), 7, 57 (2H, d, J = 9.2 Hz). *) 5.07 (1H, q, J = 7.2 Hz).

 Reference Example 44. By the same method as in Reference Example 5, starting from 1.0 g of (1S) -1 - [(2R) -2- (2,4-Difluorophenyl) -2-oxiranyl] ethanol and 1.23 g of 1- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone get 0.43 g of 1 - [(1R, 2S) -2- (2,4 -difluorophenyl) -2,3-epoxy-1-methylpropyl] - 3- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone in the form of colorless plates.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 7.2 Hz), 2.71 (1H, d, J = 4.8 Hz), 2.81 (1H, d, J = 4.8 Hz), 4.44 (2H, t, J = 12 Hz), 5.08 (1H, q, J = 7.2 Hz), 6.44 (1H, d, J = 3, 2 Hz), 6.52 (1H, d, J = 3.2 Hz), 6.78-6.95 (2H, m), 7.00 (2H, d, J = 9.2 Hz), 7 35-7.48 (1H, m); 7.57 (2H, d, J = 9.2 Hz).

 Reference Example 45. By the same method as in Reference Example 5, based on 0.73 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.73 g 4- [4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone get 0.74 g 2 - [(1R, 2S) -2- (2 , 4-difluorophenyl) -2,3-epoxy-1-methylpropyl] - 4- [4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone as colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7 Hz), 2.88 (1H, d, J = 4.6 Hz), 3.15 (1H, d, J = 4.6 Hz), 4.38 (2H, q, J = 8 Hz), 4.94 (1H, q, J = 7 Hz), 6.74-6.90 (2H, m), 7.02 (2H, d, J = 9.2 Hz), 7.36-7.50 (1H, m), 7.44 (2H, d, J = 9.2 Hz), 7.62 (1H, s) .

 Reference Example 46. By the same method as in Reference Example 5, starting from 0.94 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.16 g of 4- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone get 0.68 g of 2 - [(1R, 2S) - 2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] - 4- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -3 (2H, 4H) -1 , 2,4-triazolone as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7 Hz), 2.88 (1H, d, J = 4.6 Hz), 3.15 (1H, d, J = 4.6 Hz), 4.44 (2H, t, J = 12 Hz), 4.94 (1H, q, J = 7 Hz), 6.72-6.92 (2H, m), 7.02 (2H, dt, J = 9.2 Hz, J = 2.2 Hz), 7.30-7.50 (1H, m), 7.44 (2H, dt, J = 9.2 Hz, J = 2.2 Hz), 7.62 (1H, s).

 Reference Example 47. By the same method as in Reference Example 5, starting from 0.70 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.17 g of 4- [4- (2,2,3,3,4,4,5,5-octafluoropentoxy) phenyl] -3 (2H, 4H) - 1,2,4-triazolone get 0.18 g of 2- [ (1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -4- [4- (2,2,3,3,4,4,5,5-octafluoropentoxy ) phenyl] -3 (2H, 4H) -1,2,4-triazolone as a colorless viscous oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d, J = 7 Hz), 2.88 (1H, d, J = 5 Hz), 3.16 (1H, d, J = 5 Hz ), 4.49 (2H, t, J = 13 Hz), 4.95 (1H, q, J = 7 Hz), 6.10 (1H, tt, J = 52, 5.4 Hz), 6, 75-6.90 (2H, m), 7.04 (2H, d, J = 9.0 Hz), 7.25-7.42 (1H, m), 7.45 (2H, d, J = 9.0 Hz), 7.62 (1H, s).

Reference Example 48. By the same method as in Reference Example 5, starting from 0.971 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.0 g 2 - [4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone get 0.825 g of 4 - [(1R, 2S) -2- (2,4-difluorophenyl ) -2,3-epoxy-1-methylpropyl] - 2- [4- (2,2,2-trifluoroethoxy) phenyl] -3- (2H, 4H) -1,2,4-triazolone in the form of colorless prisms. T. pl. 118-119 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, d, J = 7.2 Hz), 2.73 (1H, d, J = 4.2 Hz), 2.77 (1H, d, J = 4.2 Hz), 4.37 (2H, q, J = 8.2 Hz), 5.00 (1H, q, J = 7.2 Hz), 6.81-7.02 (2H, m), 7.00 (2H, d, J = 9.2 Hz), 7.31-7.50 (1H, m), 7.59 (1H, s), 7.93 (2H, d, J = 9.2 Hz).

Reference Example 49. By the same method as in Reference Example 5, based on 0.98 g of (1S) -1 - [(2R) -2- (2,4-diferephenyl) -2-oxiranyl] ethanol and 1.04 g 2- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone get 0.882 g 4 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -2- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -3 (2H, 4H) -1,2 , 4-triazolone in the form of colorless prisms. Mp 128-129 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, d, J = 7.2 Hz), 2.73 (1H, d, J = 4.2 Hz), 2.77 (1H, d, J = 4.2 Hz), 4.44 (2H, t, J = 12.2 Hz), 5.01 (1H, q, J = 7.2 Hz), 6.80-7.01 (2H, m), 7.01 (2H, d, J = 9.2 Hz), 7.32-7.49 (1H, m), 7.59 (1H, s), 7.94 (2H, d, J = 9.2 Hz).

 Reference Example 50. By the same method as in Reference Example 5, based on 345 mg of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 410 mg of 2- [ 4- (2,2,3,3,4,4,5,5-octafluoropentoxy) phenyl] -3- (2H, 4H) - 1,2,4-triazolone get 371 mg 4 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -2- [4- (2,2,3,3,4,4,5,5-octafluoropentoxy) phenyl] -3 (2H, 4H) - 1,2,4-triazolone as colorless prisms.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, d, J = 7 Hz), 2.73 (1H, d, J = 4.2 Hz), 2.77 (1H, d, J = 4.2 Hz), 4.49 (2H, t, J = 13 Hz), 5.00 (1H, d, J = 7 Hz), 6.12 (1H, tt, J = 52, 5.4 Hz ), 6.80-7.01 (2H, m), 7.01 (2H, d, J = 9.2 Hz), 7.30-7.50 (1H, m), 7.59 (1H, s), 7.94 (2H, d, J = 9.2 Hz).

Reference Example 51. By the same method as in Reference Example 5, starting from 0.975 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.13 g of 2 - [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone, 0.847 g of 4 - [(1R, 2S) -2- (2,4 -difluorophenyl) -2,3-epoxy-1-methylpropyl] - 2- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -triazolone in the form of colorless prisms. Mp 116-117 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, d, J = 7.2 Hz), 2.73 (1H, d, J = 4.2 Hz), 2.77 (1H, d, J = 4.2 Hz), 4.37 (2H, tt, J = 11.8, 1.6 Hz), 5.00 (1H, q, J = 7.2 Hz), 6.08 (1H, tt, J = 53, 5Hz), 6.79-7.04 (2H, m), 6.99 (2H, d, J = 9.4 Hz), 7.32-7.49 (1H, m) 7.59 (1H, s); 7.93 (2H, d, J = 9.4 Hz).

Reference Example 52. By the same method as in Reference Example 5, starting from 1.15 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.27 g 2- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone get 1.20 g 4 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] - 2- [4-1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4- triazolone in the form of colorless needles. T. pl. 105-106 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, d, J = 7.2 Hz), 2.74 (1H, d, J = 4.4 Hz), 2.77 (1H, d, J = 4.4 Hz), 5.01 (1H, q, J = 7.2 Hz), 5.92 (1H, tt, J = 53, 2.8 Hz), 6.81-7.01 ( 2H, m), 7.28 (2H, d, J = 9.2 Hz), 7.30-7.49 (1H, m), 7.61 (1H, s), 8.04 (2H, d , J = 9.2 Hz).

 Reference Example 53. 2,4-Difluoroaniline (25 g) and 25.2 g of pyridine are dissolved in 200 ml of dichloromethane, to which 33.3 g of phenyl chloroformate are added dropwise under ice-cooling. After stirring under ice cooling for 30 minutes, the reaction solution was washed with water and then dried by evaporation of the solvent to obtain a mixture of phenyl 2,4-difluorophenylcarbamate and pyridine. To the mixture was added 30.7 g of 2- (diethoxy) ethylamine and the mixture was stirred at room temperature. The crystals were separated by filtration and washed with petroleum ether to obtain 37.8 g of N- (2,2-diethoxyethyl) -N '- (2,4-difluorophenyl) urea as colorless crystals.

This urea (37.5 g) was dissolved in a mixture of 560 ml of methanol and 280 ml of water, then 0.48 M hydrochloric acid was added and the resulting mixture was stirred for three days at room temperature. The reaction solution was concentrated under reduced pressure. The separated crystals were washed with a mixture of water and methanol (5: 1) to obtain 22.8 g of 1- (2,4-difluorophenyl) -2 (1H, 3H) -imidazolone as a colorless powder. Mp 192-194 ^o C.

 Calculated,%: C 55.11; H 3.08; N, 14.28.

C ₉ H ₆ F ₂ N ₂ O.

 Found,%: C 55.14; H 3.29; N, 14.18.

 Reference Examples 54-63 Derivatives of imidazolone are presented in table. 1 and 2, were obtained in the same manner as in reference example 53.

Reference Example 64
10 g (53.4 mmol) of 4-trifluoromethylphenylisocyanate are added dropwise to diethylacetal aminoacetaldehyde (7.8 ml, 53.6 mmol) at 5 ^° C over 5 minutes. The reaction solution was stirred for 1 h at room temperature. The crystals thus obtained were collected by filtration and washed with hexane to obtain 16.2 g of 1- (2,2-diethoxyethyl) -3- (4-trifluoromethylphenyl) urea (95%) as a colorless powder.

1- (2,2-Diethoxyethyl) -3- (4-trifluoromethylphenyl) urea (9.2 g, 28.7 mmol) is dissolved in a mixture of 113 ml of methanol and 57 ml of water. To the reaction solution was added 67.5 ml of 0.48 N. hydrochloric acid and the mixture was stirred for 48 hours at room temperature. Sodium hydroxide was added to the reaction solution until a pH of 7 was reached, followed by concentration under reduced pressure. The residue was extracted with ethyl acetate (100 ml x 4). The extracts are combined, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and the solvent is distilled off. The resulting crystals were recrystallized from ethyl acetate-diisopropylethyl ether to obtain 4.87 g of 1- (4-trifluoromethylphenyl) -2 (1H, 3H) -imidazolone (74%) as colorless prisms. Mp 170-171 ^o C.

 Reference Example 65

 4-Trifluoromethoxyaniline (20 g) and 9.8 g of pyridine are dissolved in 150 ml of ethyl acetate, and 19.5 g of phenyl chloroformate are added under ice-cooling. After stirring for 15 minutes with ice cooling, the reaction solution was washed with water, dried and the solvent was distilled off under reduced pressure. The separated crystals were washed with hexane to obtain 34.1 g of phenyl 4-trifluoromethoxycarbamate as colorless crystals.

 This carbamate (15 g) and 6 ml of hydrazine hydrate were stirred in 50 ml of ethanol for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was washed with cold ethyl acetate to obtain 11.7 g of 4- (4-trifluoromethoxyphenyl) semicarbazide as colorless crystals.

After stirring 7.0 g of this semicarbazide and 15.5 g of formamidine acetate in 150 ml of dimethylformamide at room temperature for 30 minutes, 8.9 g of acetic acid was added and the mixture was heated at 80 ^° C. for 6 hours. The solvent was removed by distillation at reduced pressure. Ethyl acetate and saturated aqueous sodium chloride were added to the residue. The organic layer was dried and concentrated, and the residue was recrystallized from ethyl acetate-hexane to give 4- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone as colorless crystals (3.44 g). Mp 193-195 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 7.37 (2H, d, J = 9 Hz), 7.63 (2H, dt, J = 9 Hz, J = 2 Hz), 7.73 (1H, d , J = 1.4 Hz), 10.23 (1H, br).

 Reference Examples 66-84 In the same manner as in Reference Example 65, the triazolone derivatives shown in Table 1 were prepared. 3-5.

Reference Example 85. 35.6 ml of triethylamine (255 mol) and 28.8 ml of phenylchloroformate (230 mmol) are added to a solution of 3-methylbutylamine (20 g, 229 mol) in 840 ml of dichloromethane at 0 ^° C. The mixture was stirred for 3 hours at room temperature. After distilling off the solvent under reduced pressure, 200 ml of ethyl acetate and 200 ml of water are added to the residue. The organic layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml x 3). The organic layers are combined, washed with water and a saturated solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated, the crystals were separated by filtration and washed with petroleum ether to obtain 39.5 g of phenyl 3-methylbutylcarbamate (83%) as colorless crystals.

 To a solution of 3-methylbutylcarbamate (18.5 g, 8.9 mmol) in 210 ml of dioxane was added 22 ml of hydrazine hydrate and the mixture was refluxed for 3 hours. After cooling, the solvent was evaporated under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate. To the solution add a solution of 4 N. hydrochloric acid - ethyl acetate (22 ml) and the mixture was stirred for 1 h at room temperature. The precipitate was collected by filtration, washed with ethyl acetate (50 ml x 2) and dried to obtain 14.8 g of 4- (3-methylbutyl) semicarbazide hydrochloride (91%) as a white powder.

A mixture of 13.0 g of 4- (3-methylbutyl) semicarbazide hydrochloride (71.6 mmol) and 60 ml of ethyl formate was stirred for 2 hours at 110 ^° C. After cooling, the mixture was subjected to silica gel column chromatography (eluent, ethyl acetate: hexane = 1: 2 - 2: 1 - ethyl acetate δ ethyl acetate: methanol = 10: 1). The desired fractions are concentrated. The crystals thus obtained were recrystallized from ethyl acetate-petroleum ether to give 7.0 g of 4- (3-methylbutyl) -3 (2H, 4H) -1,2,4-triazolone (63%) as colorless needles. Mp 78-79 ^o C.

¹ H-NMR (CDCl ₃ ) _ →: 0.96 (6H, d, J = 6.4 Hz), 1.53-1.72 (3H, m), 3.66 (2H, t, J = 7.4 Hz), 7.39 (1H, s).

 Calculated,%: C 54.17; H 8.44; N, 27.07.

C ₇ H ₁₃ N ₃ O.

 Found,%: C 54.14; H 8.47; N, 27.14.

 Reference Example 86. To a mixture of 5.0 g of 4- (trifluoromethyl) phenylhydrazine (28.4 mmol), 31 ml of water and 3.1 ml of concentrated hydrochloric acid, 2.9 g of gliocylic acid hydrate (31.4 mmol) was added, and the mixture was stirred for 1 h at room temperature. The precipitate thus obtained was separated and collected by filtration, washed with water and dried over phosphorus pentoxide to obtain 6.26 g of 4- (trifluoromethyl) phenylhydrazonoacetic acid (95%) as a pale yellow powder.

4- (trifluoromethyl) phenylhydrazonoacetic acid (6.26 g, 27 mmol) is suspended in 176 ml of toluene and 4.0 ml of triethylamine (28.7 mmol) and 6.1 ml of diphenylphosphorylazide (28.3 mmol) are added, and the resulting mixture stirred for 1 h at 120 ^o C. After cooling, the reaction solution was extracted with 200 ml of an aqueous solution of potassium hydroxide (10%). The aqueous extract was acidified with concentrated hydrochloric acid to pH 1, the crystals thus obtained were separated, washed with water and hexane and dried over phosphorus pentoxide to obtain 4.48 g of 2- (4-trifluoromethylphenyl) -3 (2H, 4H) -1.2, 4-triazolone as a colorless powder. Mp 221 ^o C.

 Reference Examples 87-94

 In the same way as in reference example 86, were obtained triazolone derivatives, are presented in table. 6.

 Reference Example 95

In the same manner as in Reference Example 64, 1- (4-fluorophenyl) -2 (1H, 3H) -imidazolone was obtained. Mp 166-167 ^o C.

Reference Example 96. 5.36 ml of azidotrimethylsilane (39.9 mmol) was added to 4-trifluoromethylphenyl isocyanate (2.89 ml, 20.2 mmol) and the mixture was stirred at 110 ^° C. for 24 hours. After cooling, the mixture was chromatographed on silica gel column (eluent - ethyl acetate: hexane = 1: 1 - 2: 1 δ ethyl acetate) with the selection of the desired fraction, which is concentrated. The resulting crystals were recrystallized from ethyl acetate-hexane to give 3.64 g of 1- (4-trifluoromethylphenyl) -5 (1H, 4H) -tetrazolone (78%) as colorless needles. Mp 191-192 ^o C.

 Reference Examples 97-104 In the same manner as in Reference Example 96, the triazolone derivatives shown in Table 1 were prepared. 7.

Reference Example 105. 1- [4- (1,1,2,2-Tetrafluoroethoxy) phenyl] semicarbazide (6.0 g) and 10.6 g of hydrochloride acetamidine are dissolved in 100 ml of dimethylformamide. The solution was stirred for 1 h at room temperature. After adding 6.6 g of acetic acid, the reaction solution was heated at 80 ^° C. for 7 hours and concentrated under reduced pressure. The residue was dissolved in a mixture of 200 ml of ethyl acetate and 40 ml of water. The separated organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried and the solvent was distilled off. The residue was recrystallized from ethyl acetate to give 3.6 g of 5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone as colorless needles. T.pl. 204-205 ^o C.

¹ H-NMR (DMSO-d ₆ ) _ →: 2.08 (3H, s), 6.84 (1H, tt, J = 51.8 Hz, J = 3.2 Hz), 7.43 (2H , d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz), 11.57 (1H, s).

Reference Example 106. By the same method as in Reference Example 105, 5-methyl-4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2 is obtained, 4-triazolone. Mp 206-207 ^o C.

 Reference Example 107. 4-Chlorophenylhydrazine hydrochloride (5.0 g) and 3.4 g of sodium acetate are dissolved in a mixture of 50 ml of water and 25 ml of ethanol, to which 1.69 g of an 80% aqueous solution of acetaldehyde obtained is added dropwise. the mixture is stirred at room temperature for 30 minutes. After adding 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, dried and the solvent was distilled off to obtain 4-chlorophenylhydrazone acetaldehyde as an oil.

 Hydrazone is dissolved in 15 ml of acetic acid, 1.82 g of an aqueous suspension of sodium cyanate are added, the mixture is stirred for 1 h at room temperature. The precipitated crystals are collected by filtration and washed with water to obtain 4.8 g of 2- (4-chlorophenyl) -5-methyl-1,2,4-triazolisin-3-one in the form of a red-brown powder.

A mixture of 1.0 g of 2- (4-chlorophenyl) -5-methyl-1,2,4-triazolizin-3-one, a 50% aqueous solution of 2.28 g of sodium hydroxide and 0.11 g of tributylammonium bromide in 25 ml toluene is stirred for 4 hours at 60 ^° C. After cooling, the reaction mixture is diluted with 25 ml of water. The aqueous layer was separated by acidification with concentrated HCl. Precipitated crystals were collected by filtration and recrystallized from ethyl acetate-diisopropyl ether to obtain 0.56 g of 2- (4-chlorophenyl) -5-methyl-3 (2H, -4H) -1,2,4-triazolone as colorless needles. Mp 218-219 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 7.40 (2H, tt, J = 9.2 Hz, J = 2.2 Hz), 7.91 (2H, tt, J = 9.2 Hz, J = 2.2 Hz), 11.65 (1H, br).

Reference Example 108. By the same method as in Reference Example 107, 5-methyl-2- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone is obtained. Mp 213-214 ^o C.

Reference Example 109. By the same method as in Reference Example 5, starting from 0.44 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.48 g 1- [4- [4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1-piperazinyl] phenyl] - 2 (1H, 3H) -imidazolone, 0.11 g 1 - [( 1R, 2S) -2- (2,4-difluorophenyl) - 2,3-epoxy-1-methylpropyl] -3- [4- [4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] - 1-piperazinyl] phenyl] -2 (1H, 3H) -imidazole in the form of a colorless powder,
¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 7.2 Hz), 2.70 (1H, d, J = 4.8 Hz), 2.81 (1H, d, J = 4.8 Hz), 3.22-3.40 (8H, m), 4.31 (2H, t, J = 12 Hz), 5.07 (1H, q, J = 7.2 Hz) , 6.07 (1H, tt, J = 53, 5.2 Hz), 6.40 (1H, d, J = 3.2 Hz), 6.50 (1H, d, J = 3.2 Hz) 6.70-7.03 (8H, m); 7.22-7.51 (3H, m).

 Reference Example 110. By the same method as in Reference Example 5, starting from 0.31 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.50 g 4- [4- [4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1-piperazinyl] phenyl] - 3 (2H, 4H) -1,2,4-triazolone get 0, 15 g 2 - [(1R, 2S) -2- (2,4-difluorophenyl) 2,3-epoxy-1-methylpropyl] -4- [4- [4- [4- (2,2,3, 3-tetrafluoropropoxy) phenyl] - 1-piperazinyl] phenyl] -3 (2H, 4H) -triazolone as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7.0 Hz), 2.88 (1H, d, J = 5 Hz), 3.16 (1H, d, J = 5 Hz), 3.22-3.39 (8H, m), 4.31 (2H, t, J = 12.2 Hz), 4.96 (1H, q, J = 7.0 Hz), 6 07 (1H, tt, J = 53, 5.0 Hz), 6.75-7.03 (8H, m), 7.23-7.40 (3H, m), 7.59 (1H, s )

 Reference Example 111. By the same method as in Reference Example 5, based on 0.35 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.31 g of 1- [4- (2,2,2-trifluoroethoxy) phenyl] -5 (1H, 4H) -1,2,4-tetrazolone, a mixture of (3: 2, 0.22 g) 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2, 3-epoxy-1-methylpropyl] -4- [4- (2,2,2-trifluoroethoxy) phenyl] -5 (1H, 4H) - 1, 2,4-tetrazolone and (2R) -2- (2,4-difluorophenyl) -2 - [(1R) -1- [1- [4- (2,2,2-trifluoroethoxy) phenyl] -1H-tetrazole -5-yloxy] ethyl] oxirane as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.55 (d, J = 7 Hz), 1.60 (d, J = 8 Hz), 2.93 (d, J = 4.5 Hz), 2.96 (d, J = 4.8 Hz), 3.17 (d, J = 4.5 Hz), 3.20 (d, J = 4.8 Hz), 4.40 (q, J = 8 Hz) , 4.44 (q, J = 8 Hz), 4.93 (q, J = 8 Hz), 5.31 (q, J = 7 Hz), 6.77-6.95 (m), 7, 06 (d, J = 9.2 Hz), 7.09 (d, J = 9.2 Hz), 7.27-7.45 (m), 7.61 (d, J = 9.2 Hz) 7.86 (d, J = 9.2 Hz).

 Reference Example 112. By the same method as in Reference Example 5, based on 1.049 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.17 g of 1 - [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -5 (1H, 4H) -tetrazolone 1.28 g of 1 - [(1R, 2S) -2- (2,4-difluorophenyl) - are obtained 2,3-epoxy-1-methylpropyl] - 4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -5 (1H, 4H) tetrazolone as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.61 (3H, d, J = 7 Hz), 2.93 (1H, d, J = 4.4 Hz), 3.17 (1H, d, J = 4.4 Hz), 4.93 (1H, q, J = 7 Hz), 5.94 (1H, tt, J = 52.8, 2.6 Hz), 6.75-6.94 (2H, m), 7.24-7.40 (1H, m), 7.34 (2H, d, J = 9 Hz), 7.98 (2H, d, J = 9 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3060, 1734, 1618, 1599, 1510, 1427.

 Reference Example 113. By the same method as in Reference Example 5, starting from 0.962 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.19 g of 1 - [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -5 (1H, 4H) -tetrazolone 1.31 g of 1 - [(1R, 2S) -2- (2,4-difluorophenyl ) -2,3-epoxy-1-methylpropyl] - 4- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -5 (1H, 4H) -tetrazolone as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.60 (3H, d, J = 7 Hz), 2.92 (1H, d, J = 4.4 Hz), 3.16 (1H, d, J = 4.4 Hz), 4.46 (2H, dt, J = 12, 1 Hz), 4.92 (1H, q, J = 7 Hz), 6.75-6.93 (2H, m), 7 05 (2H, d, J = 9.2 Hz), 7.20-7.38 (1H, m), 7.86 (2H, d, J = 7 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3060, 1732, 1618, 1601, 1558, 1516, 1427.

 Reference Example 114. In the same manner as in Reference Example 5, starting from 0.988 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 1.55 g 1 - [4- (2,2,3,3,4,4,5,5-octafluoropentoxy) phenyl] -5 (1H, 4H) tetrazolone gave a mixture (7: 3, 1.72 g) 1 - [(1R , 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -4- [4- (2,2,3,3, -4,4,5,5-octafluoropentoxy) phenyl] -5 (1H, 4H) - tetrazoline and (2R) -2- (2,4-difluorophenyl) -2 - [(1R) -1- [1- [4- (2,2,3,3, 4,4,5,5-octaphthopentoxy) phenyl] -1H-tetraeol-5-yloxy] ethyl] oxirane as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.55 (dd, J = 6.6, 1.5 Hz), 1.60 (d, J = 7.2 Hz), 2.93 (d, J = 4.5 Hz), 2.95 (d, J = 4.8 Hz), 3.17 (d, J = 4.5 Hz), 3.20 (d, J = 4.8 Hz), 4, 51 (t, J = 12.9 Hz), 4.55 (t, J = 12.8 Hz), 4.93 (q, J = 7.2 Hz), 5.31 (q, J = 7, 2 Hz), 6.10 (tt, J = 52.5.5 Hz), 6.11 (tt, J = 52.5.3 Hz), 6.74-6.94 (m), 7.06 (d, J = 9 Hz), 7.09 (d, J = 9 Hz), 7.28-7.45 (m), 7.61 (d, J = 9 Hz), 7.86 (d, J = 9 Hz).

 Reference Example 115. By the same method as in Reference Example 5, starting from 0.50 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.61 g of 5-methyl-4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone get 0.45 g of 2 - [(1R, 2S ) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -5-methyl-4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) - 1,2,4-triazolone as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 7.2 Hz), 2.11 (3H, s), 2.87 (1H, d, J = 4.8 Hz) , 3.17 (1H, d, J = 4.8 Hz), 4.38 (2H, t, J = 11.8 Hz), 4.94 (1H, q, J = 7.2 Hz), 6 06 (1H, tt, J = 53 Hz, J = 4.7 Hz), 6.74-6.90 (2H, m), 7.02 (2H, dt, J = 9.2 Hz, J = 2.6 Hz), 7.18 (2H, dt, J = 9.2 Hz, J = 2.6 Hz), 7.28-7.43 (1H, m).

 Reference Example 116. By the same method as in Reference Example 5, based on 0.50 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.58 g of 5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) - 1,2,4-triazolone get 0.46 g of 2 - [(1R, 2S ) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) - 1,2,4-triazolone as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, d, J = 7 Hz), 2.15 (3H, s), 2.87 (1H, d, J = 4.6 Hz), 3 , 18 (1H, d, J = 4.6 Hz), 4.94 (1H, q, J = 7 Hz), 5.94 (1H, tt, J = 2.6 Hz), 6.74-6 90 (2H, m); 7.25-7.42 (5H, m).

 Reference Example 117. By the same method as in Reference Example 5, starting from 0.70 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.62 g 2- (4-chlorophenyl) -5-methyl-3 (2H, 4H) -1,2,4-triazolone get 0.28 g of 2- (4-chlorophenyl) -4 - [(1R, 2S) -2 - (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -5-methyl-3 (2H, 4H) -1,2,4-triazolone as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.55 (3H, d, J = 7.2 Hz), 2.24 (3H, s), 2.94 (1H, d, J = 4.2 Hz) , 3.16 (1H, d, J = 4.2 Hz), 4.81 (1H, q, J = 7.2 Hz), 6.78-6.93 (2H, m), 7.30- 7.46 (1H, m), 7.36 (2H, d, J = 9 Hz), 7.90 (2H, d, J = 9Hz).

 Reference Example 118. By the same method as in Reference Example 5, from 0.50 g of (1S) -1 - [(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol and 0.52 g of 5-methyl-2- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone get 0.13 g of 4 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] - 5-methyl-2- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone as a colorless viscous oil.

¹ H-NMR (CDCl ₃ ) δ: 1.55 (3H, d, J = 7 Hz), 2.24 (3H, s), 2.92 (1H, d, J = 4 Hz), 3.16 (1H, d, J = 4 Hz), 4.81 (1H, q, J = 7 Hz), 6.78-6.91 (2H, m), 7.25 (2H, d, J = 9 Hz ), 7.33-7.44 (1H, m), 7.97 (2H, d, J = 9 Hz).

Working Example 1. Mixture of 300 mg (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2 - [(1H-1,2,4-thiazol-1-yl) methyl] oxirane and 2 , 77 g of 1-phenyl-2-trimethylsilyloxyimidazole is stirred under argon at 180 ^° C. for 4 hours. After cooling, 50 ml of chloroform and 50 ml of water are added to the reaction solution. The separated aqueous layer was further extracted with 10 ml of chloroform. The organic extracts are combined, washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane = 1: 2 to 1: 1) to obtain 16 g of 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -1-methyl- 3- (1H-1,2,4-triazol-1-yl) - 2-trimethylsilyl-hydroxypropyl] -3-phenyl-2 (1H, 3H) - imidazolone.

¹ H-NMR (CDCl ₃ ) δ: 0.28 (9H, s), 1.09 (3H, d, J = 7 Hz), 4.35 (1H, d, J = 15 Hz), 5.06 (1H, q, J = 7 Hz), 5.28 (1H, dd, J = 15, 2 Hz), 6.62 (1H, d, J = 3.2 Hz), 6.71 (1H, d , J = 3.2 Hz), 6.75-6.91 (2H, m), 7.25-7.65 (6H, m), 7.67 (1H, s), 7.89 (1H, s).

 To a solution of 118 mg of the title compound in 6 ml of tetrahydrofuran was added 77 mg of tetrabutylammonium trihydrate fluoride and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent, ethyl acetate: hexane = 1: 1 to 21: 1) to obtain 83 g of [1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2-hydroxy -1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3-phenyl-2 (1H, 3H) -imidazolone (Compound 1) as a yellow powder.

¹ H-NMR (CDCl ₃ ) δ; 1.21 (3H, d, J = 7 Hz), 4.20 (1H, d, J = 14.4 Hz), 4.95 (1H, q, J = 7 Hz), 5.11 (1H, d, J = 14.4 Hz), 5.64 (1H, s), 6.66 (1H, s, J = 3.2 Hz), 6.73 (1H, d, J = 3.2 Hz) 6.75-6.87 (2H, m), 7.40-7.69 (6H, m), 7.72 (1H, s), 7.86 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 1684, 1616, 1558, 1522, 1498, 1320.

SIMS (m / z): 412 (M + H) ⁺ .

 Working Example 2. 1 - [(1R, 2S) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (4-trifluoromethylphenyl) -2 (1H, 3H) -imidazolone (compound 2).

 60% sodium hydride in oil (65 mg) is dispersed in 4 ml of dimethylformamide, to which 118 mg of 1,2,4-triazole are added under ice-cooling.

The mixture was stirred at room temperature for 10 minutes. A solution of 1 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- (4-trifluoromethylphenyl) -2 (1H, 3H) -imidazoline obtained as indicated in Reference Example 5, in 2 ml of dimethylformamide, and the final mixture was heated at 50 ^° C. for 5 hours.

 After cooling, the reaction solution was fractionated by adding 8 ml of cold water and 40 ml of ethyl acetate, and the separated aqueous layer was extracted twice with ethyl acetate.

 The ethyl acetate extracts are combined, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent, ethyl acetate: hexane = 1: 1 to 2: 1 to ethyl acetate) to obtain 350 mg of compound 2 as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.2 Hz), 4.19 (1H, d, J = 14.2 Hz), 5.00 (1H, q, J = 7.2 Hz), 5.11 (1H, d, J = 14.2 Hz), 5.46 (1H, s), 6.71 (1H, d, J = 3.2 Hz), 6 , 83 (1H, d, J = 3.2 Hz), 6.72-6.90 (2H, m), 7.40-7.56 (1H, m), 7.72 (2H, d, J = 8.4 Hz), 7.75 (1H, s), 7.83 (2H, d, J = 8.4 Hz), 7.84 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3404, 3383, 3000, 1693, 1618, 1599, 1524, 1500, 1429, 1327.

 Calculated,%: C 55.12; H 3.78; N, 14.61.

C ₂₂ H ₁₈ F ₅ N ₅ O ₂ .

 Found,%: C 54.81; H 3.97; N, 14.39.

 Working examples 3-19. The following compounds are obtained in the same manner as in working example 2.

 Working Example 3.1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3-methyl-2 (1H, 3H) -imidazolone (compound 3), colorless oil. Yield 88 mg (68%).

¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 6.8 Hz), 3.45 (3H, s), 4.69 (1H, d, J = 14.4 Hz) 5.05 (1H, dd, J = 14.4, 1.4 Hz), 5.34 (1H, q, J = 6.8 Hz), 5.60 (1H, s), 6.55 ( 1H, d, J = 1.6 Hz), 6.64 (1H, d, J = 1.6 Hz), 6.70-6.88 (2H, m), 7.45-7.62 (1H , m), 7.70 (1H, s), 8.06 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{neat}}{\text{max}}$ cm ^-1 : 3113, 1660, 1618, 1597, 1535.

SIMS (m / z): 350 (M + H) ⁺ .

 Working Example 4. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (4-fluorophenyl) -2 (1H, 3H) -imidazolone (Compound 4), colorless powder. Yield 971 mg (74%).

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7 Hz), 4.20 (1H, d, J = 14.2 Hz), 4.95 (1H, q, J = 7 Hz), 5.10 (1H, d, J = 14.2 Hz); 5.58 (1H, br), 6.60 (1H, d, J = 3.2 Hz), 6.74 (1H, d, J = 3.2 Hz), 6.70-6.88 (2H , m), 7.05-7.20 (2H, m), 7.40-7.65 (3H, m), 7.73 (1H, s), 7.85 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3147, 3126, 1687, 1618, 1599, 1513.

SIMS (m / z): 430 (M + H) ⁺ .

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ -24.8 ^o (C = 0.4, CH ₃ OH).

Working Example 5.1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (2,4-difluorophenyl) -2 (1H, 3H) -imidazolone (compound 5), a colorless crystalline powder. Yield 416 mg (66%). T. pl. 134-136 ^o C.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7 Hz), 4.19 (1H, d, J = 14.4 Hz), 4.95 (1H, q, J = 7 Hz), 5.11 (1H, d, J = 14.4 Hz), 5.52 (1H, br), 6.52 (1H, t, J = 2.6 Hz), 6.70-6 86 (3H, m), 6.92-7.06 (2H, m), 7.40-7.68 (2H, m), 7.74 (1H, s), 7.85 (1H, s )

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 1693, 1614, 1515, 1428, 1269, 1248.

 Working Example 6. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-fluorophenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 6), colorless powder. Yield 532 mg (53%).

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7 Hz), 4.36 (1H, d, J = 14.2 Hz), 5.01 (1H, d, J = 14.2 Hz), 5.08 (1H, q, J = 7 Hz), 5.44 (1H, s), 6.72-6.90 (2H, m), 7.12-7.31 ( 2H, m), 7.48-7.65 (3H, m), 7.69 (1H, s), 7.76 (1H, s), 7.94 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3420, 3130, 3000, 1703, 1620, 1599.

SIMS (m / z): 431 (M + H) ⁺ .

 Calculated,%: C 53.57; H 4.27; N, 18.74.

C ₂₀ H ₁₇ F ₃ N ₆ O ₂ • H ₂ O.

 Found,%: C 53.95; H 4.14; N, 18.45.

 Working Example 7. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (4-methoxyphenyl) -2 (1H, 3H) -imidazolone (compound 7), colorless powder. Yield 663 mg (90%).

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.2 Hz), 3.83 (3H, s), 4.21 (1H, d, J = 14.2 Hz) 4.92 (1H, q, J = 7.2 Hz), 5.09 (1H, d, J = 14.2 Hz), 5.71 (1H, br), 6.58 (1H, d, J = 3.2 Hz), 6.68 (1H, d, J = 3.2 Hz), 6.70-6.88 (2H, m), 6.97 (2H, d, J = 9 Hz) 7.40-7.60 (1H, m), 7.50 (2H, d, J = 9 Hz), 7.72 (1H, s), 7.88 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3500, 3120, 3000, 1680, 1614, 1516.

SIMS (m / z): 442 (M + H) ⁺ .

 Working Example 8. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-methoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 8), a colorless powder. Yield 672 mg (65%).

¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 7 Hz), 3.85 (3H, s), 4.35 (1H, d, J = 14.4 Hz), 5 , 02 (1H, d, J = 14.4 Hz), 5.08 (1H, q, J = 7 Hz), 5.56 (1H, s), 6.71-6.89 (2H, m) 7.01 (2H, d, J = 9 Hz), 7.45 (2H, d, J = 9 Hz), 7.50-7.64 (1H, m), 7.67 (1H, s) 7.73 (1H, s); 7.96 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3500, 3120, 3080, 1693, 1620, 1562, 1516.

SIMS (m / z): 443 (M + H) ⁺ :
Calculated,%: C 54.78; H 4.82; N, 18.25.

C ₂₁ H ₂₀ F ₂ N ₆ O ₃ • H ₂ O.

 Found,%: C 54.86; H 4.64; N, 18.06.

 Working Example 9.1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (4-trifluoromethoxyphenyl) - 2 (1H, 3H) -imidazolone (compound 9), a colorless powder. Yield 500 mg (71%).

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7 Hz), 4.19 (1H, d, J = 14.4 Hz), 4.97 (1H, q, J = 7 Hz), 5.10 (1H, d, J = 14.4 Hz), 5.51 (1H, br), 6.39 (1H, d, J = 3.2 Hz), 6.64 (1H , d, J = 3.2 Hz), 6.70-6.86 (2H, m), 7.31 (2H, d, J = 9 Hz), 7.38-7.54 (1H, m) 7.69 (2H, d, J = 9 Hz); 7.74 (1H, s); 7.84 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 1691, 1620, 1599, 1514, 1427, 1252.

 Working Example 10.2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 10), a colorless powder. Yield 420 mg (42%).

¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7.0 Hz), 4.38 (1H, d, J = 15 Hz), 5.03 (1H, d, J = 15 Hz), 5.09 (1H, q, J = 7.0 Hz), 5.35 (1H, br), 6.76-6.86 (2H, m), 7.50-7.62 ( 1H, m), 7.66-7.84 (5H, m), 7.87 (1H, s), 7.94 (1H, s).

 Working Example 11. 4 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- (4-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 11), a colorless powder. Yield 304 mg (24%).

¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7.2 Hz), 4.15 (1H, d, J = 14 Hz), 4.97 (1H, dq, J = 7.2, 1.4Hz), 5.08 (1H, q, J = 14 Hz), 5.56 (1H, d, J = 1.4 Hz), 6.76-6.91 (2H, m ), 7.38-7.59 (1H, m), 7.72 (2H, d, J = 8.6 Hz), 7.77 (1H, s), 7.80 (1H, s), 8 00 (1H, s), 8.20 (2H, d, J = 8.6 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3106, 1701, 1618, 1597, 1568, 1520.

 Working Example 12. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 12), a colorless powder. Yield: 790 mg (47%).

¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7 Hz), 4.37 (1H, d, J = 14.2 Hz), 5.03 (1H, d, J = 14.2 Hz), 5.09 (1H, q, J = 7 Hz), 5.41 (1H, s), 6.76-6.90 (2H, m), 7.38 (2H, d, J = 9 Hz), 7.51-7.64 (1H, m), 7.65 (2H, d, J = 9 Hz), 7.70 (1H, s), 7.81 (1H, s) 7.94 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 1711, 1620, 1562, 1516, 1500, 1427, 1259, 1209.

 Working Example 13. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl- 3- (1H-1,2,4-triazol-1-yl) propyl] 3- (4-isopropylphenyl) -2 (1H, 3H) -imidazolone (compound 13), colorless powder. Yield 200 mg (84%).

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7 Hz), 1.26 (6H, d, J = 6.8 Hz), 2.94 (1H, q, J = 6.8 Hz), 4.19 (1H, d, J = 14 Hz), 4.92 (1H, m), 5.09 (1H, d, J = 14 Hz), 5.6-5.8 (1H, br), 6.62 (1H, d, J = 3.2 Hz), 6.69 (1H, d, J = 3.2 Hz), 6.7-6.9 (2H, m) , 7.30 (2H, d, J = 8.6 Hz), 7.4-7.5 (1H, m), 7.52 (2H, d, J = 8.4 Hz), 7.71 ( 1H, s), 7.87 (1H, s).

Working Example 14. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (2,4-difluorophenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 14), colorless powder. T.pl. 111-113 ^o C. Yield 660 mg (47%).

¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, d, J = 7 Hz), 4.36 (1H, d, J = 14.4 Hz), 5.04 (1H, d, J = 14.4 Hz), 5.07 (1H, q, J = 7 Hz), 5.73 (1H, s), 6.74-6.88 (2H, m), 7.00-7.14 ( 2H, m), 7.50-7.75 (2H, m), 7.71 (1H, s), 7.73 (1H, d, J = 2.4 Hz), 7.95 (1H, s )

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 1711, 1614, 1554, 1515, 1500, 1439, 1333, 1273.

 Working Example 15. 4 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- (4-fluorophenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 15), colorless powder. Yield 545 mg (55%).

¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 7.2 Hz), 4.15 (1H, d, J = 14.2 Hz), 4.95 (1H, dq, J = 7.2, 1.6 Hz), 5.08 (1H, d, J = 14.2 Hz), 5.56 (1H, d, J = 1.6 Hz), 6.78-6, 91 (2H, m), 7.14 (2H, t, J = 9.4 Hz), 7.39-7.62 (1H, m), 7.77 (1H, s), 7.80 (1H , s), 7.95 (1H, s), 7.99 (2H, dd, J = 9.4, 4.8 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3093, 1691, 1620, 1599, 1566, 1512.

 Working example 16. By the same method as in working example 2, a reaction was carried out using a mixture of the order of 1: 1 2 - [(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1 -methylpropyl] -4- (4-isopropylphenyl) - 3 (2H, 4H) -1,2,4-triazolone and (1R) -1 - [(2R) -2- (2,4-difluorophenyl) - 2- oxiranyl] ethanol obtained in Reference Example 20 to give 2 - ((1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4- triazol-1-yl) propyl] -4- (4-isopropylphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 17) as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6.8 Hz), (3H, d, J = 7 Hz), 2.97 (1H, q, J = 6.8 Hz), 4.35 (1H, d, J = 14 Hz), 5.03 (1H, d, J = 14 Hz), 5.10 (1H, q, J = 7 Hz), 5.55 (1H , s), 6.76-6.87 (2H, m), 7.37 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8 Hz), 7 50-7.62 (1H, s), 7.68 (1H, s), 7.77 (1H, s), 7.96 (1H, s).

 Calculated,%: C 60.79; H 5.32; N, 18.49.

C ₂₃ H ₂₄ F ₂ N ₆ O ₂ .

 Found,%: C 60.48; H 5.49; N, 18.32.

 Working Example 17. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-trifluoromethylphenyl) -5 (1H, 4H) -tetrazolone (compound 18), a colorless powder. Yield 21%.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d, J = 7.2 Hz), 4.36 (1H, d, J = 14.2 Hz), 5.08 (1H, d, J = 14.2 Hz), 5.10 (1H, q, J = 7.2 Hz), 5.47 (1H, s), 6.74-6.91 (2H, m), 7.50- 7.68 (1H, m), 7.73 (1H, s), 7.80 (2H, d, J = 8.8 Hz), 7.91 (1H, s), 8.18 (2H, d , J = 8.8 Hz).

 Calculated,%: C 49.90; H 3.35; N, 20.37.

C ₂₀ H ₁₆ F ₅ N ₇ O ₂ .

 Found,%: C 49.64; H 3.35; N, 20.22.

 Working Example 18. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] - 2 (1H, 3H) -imidazolone (compound 19), colorless powder. Yield 79%.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7 Hz), 4.20 (1H, d, J = 14 Hz), 4.37 (2H, t, J = 12 Hz ), 4.94 (1H, q, J = 7 Hz), 5.09 (1H, d, J = 14 Hz), 5.55-5.74 (1H, br), 6.06 (1H, tt , J = 5, 53 Hz), 6.59 (1H, d, J = 3 Hz), 6.72 (1H, d, J = 3 Hz), 6.74-6.85 (2H, m), 7.01 (2H, d, J = 9 Hz), 7.42-7.55 (1H, m), 7.58 (2H, d, J = 9 Hz), 7.73 (1H, s), 7.86 (1H, s). Mp 124.6-125.5 ^o C.

 Calculated,%: C 53.24; H 3.91; N, 12.93.

C ₂₄ H ₂₁ F ₆ N ₅ O ₃ .

 Found,%: C 53.12; H 4.19; N, 12.76.

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ - 17.9 ^o (C = 0.3, CH ₃ OH).

 Working Example 19. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (4-benzyl-1-piperazinyl) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 21), a colorless powder. Yield 59%.

¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, d, J = 7 Hz), 2.62 (4H, t, J = 4.8 Hz), 3.25 (4H, t, J = 4.8 Hz), 3.59 (2H, s), 4.33 (1H, d, J = 14.2 Hz), 5.01 (1H, d, J = 14.2 Hz), 5.08 (1H, q, J = 7 Hz), 5.60 (1H, s), 6.72-6.91 (2H, m), 6.98 (2H, d, J = 9 Hz), 7.23 -7.45 (7H, m), 7.45-7.62 (1H, m), 7.66 (1H, s), 7.71 (1H, s), 7.96 (1H, s).

 Calculated,%: C 62.51; H 5.58; N, 18.81.

C ₃₁ H ₃₂ F ₂ N ₈ O ₂ • 0.5H ₂ O.

 Found,%: C 62.28; H 5.44; N, 18.56.

 Working Example 20. 4- [4- (4-Acetyl-1-piperazinyl) phenyl] -2 - [(1R, 2R) - 2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 23).

 To a solution of 170 mg of compound 21 in 20 ml of ethanol was added 20 mg of 10% Pd-C and the mixture was stirred at room temperature in a stream of hydrogen for 9 hours. The catalyst was filtered off and washed with 5 ml of ethanol. The filtrate and washings were combined and concentrated under reduced pressure to obtain 144 mg of 2 - [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2, 4-triazol-1-yl) propyl] -4- [4- (1-piperazinyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 22) as a pale yellow oil.

To a solution of 144 mg of compound 22 in 20 ml of methylene chloride was added 0.044 ml of triethylamine at 0 ^° C, then another 0.030 ml of acetic anhydride and the resulting mixture was stirred for 1 hour. The reaction solution was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel chromatography (eluent, ethyl acetate: methanol = 10: 1) to obtain 80 mg of compound 23 as a pale yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 7 Hz), 2.16 (3H, s), 3.15-3.35 (4H, m), 3.59- 3.88 (4H, m), 4.35 (1H, d, J = 14.4 Hz), 5.01 (1H, d, J = 14.4 Hz), 5.08 (1H, q, J = 7 Hz), 5.57 (1H, s)), 6.75-6.90 (2H, m), 7.01 (2H, d, J = 9 Hz), 7.44 (2H, d, J = 9 Hz), 7.49-7.67 (1H, s), 7.68 (1H, s), 7.73 (1H, s), 7.98 (1H, s).

 Calculated,%: C 55.20; H 5.52; N, 19.81.

C ₂₆ H ₂₈ F ₂ N ₈ O ₃ • 1,5H ₂ O.

 Found,%: C 55.55; H 5.22; N, 19.77.

 Working examples 21-50. The following compounds are obtained in the same manner as in working example 2.

Working Example 21. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- [4- (4-methoxyphenyl) - 1-piperazinyl] phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 24). Mp 204-205 ^o C. Yield 97%.

¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 7 Hz), 3.18-3.30 (4H, m), 3.30-3.46 (4H, m), 3.79 (3H, s), 4.35 (1H, d, J = 14.4 Hz), 5.01 (1H, d, J = 14.4 Hz), 5.09 (1H, q, J = 7 Hz), 5.59 (1H, s), 6.72-6.90 (2H, m), 6.87 (2H, d, J = 9.2 Hz), 6.97 (2H, d , J = 9.2 Hz), 7.06 (2H, d, J = 9.2 Hz), 7.43 (2H, d, J = 9.2 Hz), 7.50-7.66 (1H , m), 7.68 (1H, s), 7.73 (1H, s), 7.97 (1H, s).

 Calculated,%: C 61.78; H 5.35; N, 18.59.

C ₃₁ H ₃₂ F ₂ N ₈ O ₃ .

 Found,%: C 61.45; H 5.37; N, 18.29.

 Working Example 22. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (3-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 25), colorless powder. Yield 30%.

¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, d, J = 7.0 Hz), 4.36 (1H, d, J = 14.6 Hz), 5.04 (1H, d, J = 14.6 Hz), 5.09 (1H, q, J = 7.0 Hz), 5.36 (1H, s), 6.76-6.86 (2H, m), 7.5- 7.7 (4H, m), 7.78-7.90 (2H, m), 7.86 (1H, s), 7.93 (1H, s).

 Calculated,%: C 52.50; H 3.57; N, 17.49.

C ₂₁ H ₁₇ F ₅ N ₆ O ₂ .

 Found,%: C 52.64; H 3.72; N, 17.15.

 Working Example 23. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-fluorophenyl) -5 (1H, 4H) -tetrazolone (compound 26), a colorless powder. Yield 51%.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7.2 Hz), 4.35 (1H, d, J = 14.4 Hz), 5.08 (1H, d, J = 14.4 Hz), 5.10 (1H, q, J = 7.2 Hz), 5.50 (1H, s), 6.72-6.90 (2H, m), 7.15- 7.30 (2H, m), 7.50-7.68 (1H, s), 7.72 (1H, s), 7.91 (1H, s), 7.89-8.01 (2H, m).

 Calculated,%: C 50.78; H 4.04; N, 21.82.

C ₁₉ H ₁₆ F ₃ N ₇ O ₂ • H ₂ O.

 Found,%: C 50.83; H 3.71; N, 21.68.

 Working Example 24. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy 1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] - 4- (4-pyridyl) -3 (2H, 4H) - 1,2,4-triazolone (compound 27), a colorless powder. Yield 41%.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 7.2 Hz), 4.37 (1H, d, J = 14.2 Hz), 5.01 (1H, d, J = 14.2 Hz), 5.07 (1H, q, J = 7.2 Hz), 5.31 (1H, s), 6.74-6.90 (2H, m), 7.50- 7.65 (1H, s), 7.67 (1H, s), 7.69 (1H, s), 7.70 (1H, s), 7.93 (2H, d, J = 5.8 Hz ), 8.75 (2H, d, J = 5.8 Hz).

 Calculated,%: C 51.82; H 4.58; N, 22.26.

C ₁₉ H ₁₇ F ₂ N ₇ O ₂ • 1,5H ₂ O.

 Found,%: C 51.47; H 4.24; N, 22.48.

 Working Example 25. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-pyrimidinyl) -3 (2H, 4H) -1,2,4-triazolone (compound 28), a colorless powder. Yield 10%.

¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, d, J = 6.6 Hz), 4.32 (1H, d, J = 11.6 Hz), 4.78 (1H, q, J = 6.6 Hz), 4.90 (1H, d, J = 11.6 Hz), 5.41 (1H, s), 6.70-6.92 (2H, m), 7.44 ( 1H, s), 7.89 (1H, dd, J = 5.6 Hz, 1.2 Hz), 7.85-8.06 (1H, m), 8.15 (1H, s), 8, 90 (1H, d, J = 5.6 Hz), 9.10 (1H, d, J = 1.2 Hz), 9.26 (1H, s).

 Calculated,%: C 51.06; H 4.05; N, 26.47.

C ₁₈ H ₁₆ F ₂ N ₈ O ₂ • 0.5H ₂ O.

 Found,%: C 50.70; H 3.71; N, 26.62.

 Working Example 26. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (2,2,2-trifluoroethyl) -3 (2H, 4H) -1,2,4-triazolone (compound 29), a colorless powder. Yield 53%.

¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, d, J = 7.2 Hz), 4.25 (14, d, J = 14.5 Hz), 4.32 (2H, dq, J = 1.6 Hz, J = 8.6 Hz), 5.00 (1H, q, J = 7.2 Hz), 5.02 (1H, d, J = 14.5 Hz), 5.29 (1H, s), 6.72-6.88 (2H, m), 7.48-7.0 (1H, m), 7.63 (1H, s), 7.70 (1H, s), 7.93 (1H, s).

 The specified compound is treated with a solution of 4n. hydrochloric acid-ethyl acetate to obtain hydrochloride in the form of a colorless powder.

IRυ ^(KBr) cm ^-1 : 1716, 1700, 1689, 1652, 1618, 1560, 1506.

 Working Example 27. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 30), colorless powder. Yield 63%.

Mp 150-151 ^o C (isopropyl ether).

IRυ $\genfrac{}{}{0ex}{}{\text{Kbr}}{\text{max}}$ cm ^-1 : 1716, 1697, 1618, 1558, 1517, 1506.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7 Hz), 4.37 (1H, d, J = 15 Hz), 4.40 (2H, tt, J = 11, 8, 1.4 Hz) 5.02 (1H, d, J = 15 Hz), 5.47 (1H, s), 5.09 (1H, q, J = 7 Hz), 6.07 (1H, tt, J = 53 Hz, 4.8 Hz), 6.75-6.88 (2H, m), 7.07 (2H, dt, J = 9 Hz, 2.2 Hz), 7.53 (2H , dt, J = 9 Hz, 2.2 Hz), 7.50-7.64 (1H, m), 7.69 (1H, s), 7.75 (1H, s), 7.95 (1H , s).

 Calculated,%: C 50.93; H 3.72; N, 15.49.

C ₂₃ H ₂₀ F ₆ N ₆ O ₃ .

 Found,%: C 50.91; H 3.84; N, 15.47.

 Working Example 28. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (2-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 31), a colorless powder. Yield 28%.

¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, d, J = 7 Hz), 4.29 (1H, d, J = 14.2 Hz), 5.06 (1H, d, J = 14.2 Hz), 5.07 (1H, q, J = 7 Hz), 5.41 (1H, s), 6.74-6.86 (2H, m), 7.48-7.60 ( 3H, m), 7.63-7.90 (3H, m), 7.70 (1H, s), 7.97 (1H, s).

 Calculated,%: C 52.50; H 3.57; N, 17.49.

C ₂₁ H ₁₇ F ₅ N ₆ O ₂ .

 Found,%: C 52.32; H 3.76; N, 17.35.

 Working Example 29. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-isopropoxyphenyl) -3 (2H, 4H) -triazolone (compound 32), a colorless powder. Yield 80%.

¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 7.0 Hz), 1.36 (6H, d, J = 6 Hz), 4.35 (1H, d, J = 14.2 Hz), 4.58 (1H, septet, J = 6 Hz), 5.02 (1H, d, J = 14.2 Hz), 5.08 (1H, q, J = 7 Hz), 5.57 (1H, s), 6.72-6.89 (2H, m), 6.99 (2H, d, J = 9 Hz), 7.42 (2H, d, J = 9 Hz), 7.47-7.63 (1H, s), 7.67 (1H, s), 7.72 (1H, s), 7.96 (1H, s).

 Calculated,%: C 56.55; H 5.36; N, 17.20.

C ₂₃ H ₂₄ F ₂ N ₆ O ₃ • H ₂ O.

 Found,%: C 56.36; H 5.15; N, 17.26.

 Working Example 30. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (3-methylbutyl) -3 (2H, 4H) -1,2,4-triazolone (compound 33), colorless powder. Yield 53%.

¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, d, J = 6.2 Hz), 1.23 (3H, d, J = 6.8 Hz), 1.56-1.80 ( 3H, m), 3.72 (2H, t, J = 7.2 Hz), 4.20 (1H, d, J = 14.2 Hz), 4.97 (1H, d, J = 14.2 Hz), 5.02 (1H, q, J = 6.8 Hz), 5.63 (1H, s), 6.72-6.90 (2H, m), 7.45-7.62 (1H , m), 7.50 (1H, s), 7.67 (1H, s), 7.96 (1H, s).

SIMS (m / z): 407 (M + H) ⁺ .

 Working Example 31. 2- [1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] - 4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 34), colorless powder. Yield 65%.

IRυ cm ^-1 (KBr): 1710, 1691, 1620, 1564, 1511, 1276.

¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7 Hz), 4.37 (1H, d, J = 14.2 Hz), 5.02 (1H, d, J = 14.2 Hz), 5.09 (1H, q, J = 7 Hz), 5.41 (1H, s), 5.94 (1H, tt, J = 53 Hz, J = 2.8 Hz), 6.75-6.90 (2H, m), 7.38 (2H, d, J = 9 Hz), 7.50-7.70 (1H, m), 7.63 (3H, d, J = 9 Hz), 7.70 (1H, s), 7.80 (1H, s), 7.94 (1H, s).

 Working Example 32. 2- (4-Chlorophenyl) -4-1 (1R, 2R) -2- (2,4-difluorophenyl) - 2-hydroxy-1-methyl-3- (1H-1,2,4- triazol-1-yl) propyl] -3 (2H, 4H) -1,2,4-triazolone (compound 36), colorless prisms. Yield 66%.

¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 7.2 Hz), 4.14 (1H, d, J = 14.2 Hz), 4.95 (1H, dq, J = 7.2 Hz, 1.6 Hz), 5.07 (1H, d, J = 14.2 Hz), 5.54 (1H, d, J = 1.6 Hz), 6.73-6 , 89 (2H, m), 7.37-7.50 (1H, m), 7.41 (2H, d, J = 9 Hz), 7.77 (1H, s), 7.93 (1H, s), 7.96 (1H, s), 7.98 (2H, d, J = 9 Hz).

 Calculated,%: C 53.76; H 3.83; N, 18.81.

C ₂₀ H ₁₇ ClF ₂ N ₆ O ₂ .

 Found,%: C 53.93; H 4.00; N, 18.44.

 Working Example 33. 4 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 36), a colorless powder. Yield 68%.

¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7.2 Hz), 4.14 (1H, d, J = 14.4 Hz), 4.96 (1H, dq, J = 7.2, 1.6 Hz), 5.08 (1H, d, J = 14.4 Hz), 5.56 (1H, d, J = 1.6 Hz), 6.75-6, 90 (2H, m), 7.31 (2H, d, J = 9.2 Hz), 7.48-7.52 (1H, m), 7.77 (1H, s), 7.80 (1H , s), 7.97 (1H, s), 8.08 (2H, d, J = 9.2 Hz).

 Working Example 34. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-trifluoromethoxyphenyl) -5 (1H, 4H) -tetrazolone (compound 37), a colorless powder. Yield: 43%.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7.2 Hz), 4.35 (1H, d, J = 13.8 Hz), 5.08 (1H, d, J = 13.8 Hz), 5.10 (1H, q, J = 7.2 Hz), 5.51 (1H, s), 6.71-6.90 (2H, m), 7.38 ( 2H, d, J = 9.2 Hz), 7.48-7.63 (1H, m), 7.72 (1H, s), 7.91 (1H, s), 8.04 (2H, d , J = 9.2 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3400, 3010, 1722, 1684, 1618, 1599, 1510.

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ -5.7 ^° (C = 1, methanol).

 Working example 35. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] - 5 (1H, 4H) -tetrazolone (compound 38), colorless powder. Yield 57%.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, d, J = 7.2 Hz), 4.35 (1H, d, J = 14.2 Hz), 4.41 (2H, t, J = 11.8 Hz), 5.08 (1H, d, J = 14.2 Hz), 5.11 (1H, q, J = 7.2 Hz), 5.53 (1H, s), 6 09 (1H, tt, J = 53.2, 4.8 Hz), 6.75-6.90 (2H, m), 7.08 (2H, d, J = 9 Hz), 7.50- 7.68 (1H, m), 7.72 (1H, s), 7.90 (2H, d, J = 9 Hz), 7.92 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3400, 3050, 1726, 1618, 1599, 1516, 1423.

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ -2.3 ^o (C = 0.4, methanol).

 Working Example 36. 1- (4-Chlorophenyl) -4 - [(1R, 2R) -2- (2,4-difluorophenyl) - 2-hydroxy-1-methyl-3- (1H-1,2,4- triazol-1-yl) propyl] -5 (1H, 4H) -tetrazolone (compound 39), a colorless powder. Yield 46%.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7 Hz), 4.35 (1H, d, J = 14.4 Hz), 5.08 (1H, d, J = 14.4 Hz), 5.10 (1H, q, J = 7 Hz), 5.49 (1H, s), 6.72-6.91 (2H, m), 7.42-7.61 ( 1H, m), 7.50 (2H, d, J = 9 Hz), 7.72 (1H, s), 7.92 (1H, s), 7.94 (2H, d, J = 9 Hz) .

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 ; 3450, 3090, 1726, 1618, 1599, 1497.

 Calculated,%: C 49.95; H 3.75; N, 21.46.

C ₁₉ H ₁₆ ClF ₂ N ₇ O ₂ • 0.5H ₂ O.

 Found,%: C 50.08; H 3.74; N, 21.52.

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ -3.2 ^o (C = 0.5, methanol)
Working Example 37. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] - 2 (1H, 3H) -imidazolone (compound 40), colorless powder. Yield 66%.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7 Hz), 4.18 (1H, d, J = 14 Hz), 4.97 (1H, q, J = 7 Hz ), 5.10 (1H, d, J = 14 Hz), 5.4-5.6 (1H, br), 5.93 (1H, tt, J = 53, 2.8 Hz), 6.64 (1H, d, J = 3 Hz), 6.77 (1H, d, J = 3 Hz), 6.74-6.84 (2H, m), 7.30 (2H, d, J = 9 Hz ), 7.40-7.55 (1H, m), 7.67 (2H, d, J = 9 Hz), 7.74 (1H, s), 7.84 (1H, s).

 Calculated,%: C 52.38; H 3.63; N, 13.28.

C ₂₃ H ₁₉ F ₆ N ₅ O ₃ .

 Found,%: C 52.22; H 3.83; N 13.08.

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ -18.4 ^o (C = 0.6, methanol).

 Working Example 38. 1- (4-Chlorophenyl) -3 - [(1R, 2R) -2- (2,4-difluorophenyl) - 2-hydroxy-1-methyl-3- (1H-1,2,4- triazol-1-yl) propyl] -2 (1H, 3H) -imidazolone (compound 41), a colorless powder. Yield 54%.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7 Hz), 4.19 (1H, d, J = 14 Hz), 4.97 (1H, q, J = 7 Hz ), 5.10 (1H, d, J = 14 Hz), 5.42-5.65 (1H, br), 6.63 (1H, d, J = 3.2 Hz), 6.75 (1H , d, J = 3.2 Hz), 6.78-6.85 (2H, m), 7.42 (2H, d, J = 9 Hz), 7.40-7.55 (1H, m) 7.61 (2H, d, J = 9 Hz); 7.74 (1H, s); 7.85 (1H, s).

 Working Example 39. 4- (4-Chlorophenyl) -2 - [(1R, 2R) -2- (2,4-difluorophenyl) - 2-hydroxy-1-methyl-3- (1H-1,2,4- triazol-1-yl) propyl] -3 (2H, 4H) -1,2,4-triazolone (compound 42), a colorless powder. Yield 42%.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7.0 Hz), 4.36 (1H, d, J = 14 Hz), 5.02 (1H, d, J = 14 Hz), 5.08 (1H, q, J = 7.0 Hz), 5.41 (1H, s), 6.75-6.86 (2H, m), 7.47-7.63 ( 5H, m), 7.70 (1H, s), 7.79 (1H, s), 7.94 (1H).

 Working Example 40. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2,3,3,4,4,5,5-octafluoropentoxy) phenyl] - 2- (1H, 3H) -imidazolone (compound 43), a colorless powder. Yield 74%.

¹ H-NMR (CDCl ₃ ) δ; 1.20 (3H, d, J = 7.0 Hz), 4.20 (1H, d, J = 14.3 Hz), 4.49 (2H, t, J = 13 Hz), 4.94 ( 1H, q, J = 7.0 Hz), 5.09 (1H, d, J = 14.3 Hz), 5.5-5.7 (1H, br), 6.09 (1H, tt, J = 52, 5.4 Hz), 6.59 (1H, d, J = 3.2 Hz), 6.72 (1H, d, J = 3.2 Hz), 6.75-6.85 (2H , m), 7.03 (2H, d, J = 9.0 Hz), 7.42-7.54 (1H, m), 7.58 (2H, d, J = 9.0 Hz), 7 73 (1H, s), 7.85 (1H, s).

 Working Example 41. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2,2-trifluoroethoxy) phenyl] -2 (1H, 3H) - imidazolone (compound 44), a colorless crystalline powder. Yield 70%.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 6.8 Hz), 4.20 (1H, d, J = 14.2 Hz), 4.38 (2H, q, J = 8 Hz), 4.95 (1H, q, J = 6.8Hz), 5.10 (1H, d, J = 14.2 Hz), 5.60 (1H, br), 6.60 ( 1H, d, J = 3 Hz), 6.73 (1H, d, J = 3 Hz), 6.70-6.88 (2H, m), 7.03 (2H, d, J = 9 Hz) 7.40-7.55 (1H, m), 7.58 (2H, d, J = 9 Hz), 7.73 (1H, s), 7.86 (1H, s).

 Working Example 42. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] - 2 (1H, 3H) -imidazolone (compound 45), a colorless crystalline powder. Yield 79%.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7 Hz), 4.20 (1H, d, J = 14.2 Hz), 4.45 (2H, t, J = 12 Hz), 4.95 (1H, q, J = 7 Hz), 5.10 (1H, d, J = 14.2 Hz), 5.60 (1H, br), 6.60 (1H, d , J = 3 Hz), 6.74 (1H, d, J = 3 Hz), 6.65-6.85 (2H, m), 7.03 (2H, d, J = 8.8 Hz), 7.40-7.55 (1H, m), 7.59 (2H, d, J = 8.8 Hz), 7.74 (1H, s), 7.86 (1H, s).

 Working Example 43. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 46), colorless needles. Yield 59%.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7 Hz), 4.36 (1H, d, J = 14.8 Hz), 4.41 (2H, q, J = 8 Hz), 5.02 (1H, d, J = 14.8 Hz), 5.09 (1H, q, J = 7 Hz), 5.48 (1H, s), 6.74-6.90 (2H, m), 7.09 (2H, d, J = 9 Hz), 7.48-7.65 (1H, m), 7.53 (2H, d, J = 9 Hz), 7.69 (1H, s), 7.76 (1H, s), 7.95 (1H, s).

 Working Example 44. 2- [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 47), colorless needles. Yield 46%.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7 Hz), 4.36 (1H, d, J = 14.8 Hz), 4.48 (2H, t, J = 12 Hz), 5.02 (1H, d, J = 14.8 Hz), 5.09 (1H, q, J = 7 Hz), 5.48 (1H, s), 6.75-6.90 (2H, m), 7.09 (1H, d, J = 9 Hz), 7.48-7.64 (1H, m), 7.54 (2H, d, J = 9 Hz), 7.70 (1H, s), 7.76 (1H, s), 7.95 (1H, s).

 Working Example 45. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3,4,4,5,5-octafluoropentoxy) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 48), colorless powder. Yield 54%.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7.0 Hz), 4.36 (1H, d, J = 14 Hz), 4.52 (2H, t, J = 13 Hz), 5.01 (1H, t, J = 14 Hz), 5.09 (1H, q, J = 7.0 Hz), 5.48 (1H, s), 6.10 (1H, tt , J = 52, 5.4 Hz), 6.77-6.87 (2H, m), 7.09 (2H, d, J = 9.0 Hz), 7.51-7.62 (1H, m), 7.54 (2H, d, J = 9.0 Hz), 7.70 (1H, s), 7.76 (1H, s), 7.95 (1H, s).

 Working Example 46. (4 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl ] -2- [4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 49), colorless powder, Yield 68%.

¹ H-NMR δ: 1.24 (3H, d, J = 7.2 Hz), 4.15 (1H, d, J = 14.2 Hz), 4.39 (2H, q, J = 8, 2 Hz), 4.95 (1H, dq, J = 7.2, 1.6 Hz), 5.09 (1H, d, J = 14.2 Hz), 5.56 (1H, d, J = 1.6 Hz), 6.70-6.90 (2H, m), 7.03 (2H, d, J = 9.2 Hz), 7.34-7.53 (1H, m), 7, 77 (1H, s), 7.81 (1H, s), 7.94 (1H, s), 7.96 (2H, d, J = 9.2 Hz).

 Working Example 47. 4 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 50), colorless powder. Yield 53%.

¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7.2 Hz), 4.14 (1H, d, J = 14.4 Hz), 4.45 (2H, t, J = 12.2 Hz), 4.95 (1H, dq, J = 7.2, 1.6 Hz), 5.08 (1H, d, J = 14.4 Hz), 5.54 (1H, d, J = 1.6 Hz), 6.71-6.89 (2H, m), 7.03 (2H, d, J = 9 Hz), 7.34-7.52 (1H, m), 7.77 (1H, s), 7.80 (1H, s), 7.93 (1H, s), 7.96 (2H, d, J = 9 Hz).

 Working Example 48. 4 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- [4- (2,2,3,3,4,4,5,5-octafluoropentoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 51), colorless powder. Yield 37%.

¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7 Hz), 4.14 (1H, d, J = 14.4 Hz), 4.49 (2H, t, J = 13 Hz), 4.94 (1H, dq, J = 1.6 Hz), 5.08 (1H, d, J = 14.4 Hz), 5.54 (1H, d, J = 1.6 Hz ), 6.10 (1H, tt, J = 52 Hz, 5.4 Hz), 6.71-6.89 (2H, m), 7.03 (2H, d, J = 9.2 Hz), 7.34-7.51 (1H, s), 7.77 (1H, s), 7.80 (1H, s), 7.93 (1H, s), 7.95 (2H, d, J = 9.2 Hz).

 Working Example 49. 4 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-trnazol-1-yl) propyl] -2- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 52), colorless powder. Yield 81%.

¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 7 Hz), 4.14 (1H, d, J = 14.4 Hz), 4.49 (2H, t, J = 13 Hz), 4.94 (1H, dq, J = 7, 1.6 Hz), 5.08 (1H, d, J = 14.4 Hz), 5.54 (1H, d, J = 1, 6 Hz), 6.10 (1H, tt, J = 52, 5.4 Hz), 6.71-6.89 (2H, m), 7.03 (2H, d, J = 9.2 Hz) , 7.34-7.51 (1H, s), 7.77 (1H, s), 7.80 (1H, s), 7.93 (1H, s), 7.95 (2H, d, J = 9.2 Hz).

 Working example 50. 4 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 53), colorless powder. Yield 57%.

¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7.2 Hz), 4.14 (1H, d, J = 14.2 Hz), 4.95 (1H, dq, J = 7.2, 1.6 Hz), 5.08 (1H, d, J = 14.2 Hz), 5.55 (1H, d, J = 1.6 Hz), 5.93 (1H, tt, J = 53, 2.8 Hz), 6.71-6.90 (2H, m), 7.30 (2H, d, J = 9.2 Hz), 7.34-7.51 (1H , m), 7.77 (1H, s), 7.80 (1H, s), 7.96 (1H, s), 8.06 (2H, d, J = 9.2 Hz).

Working Example 51. 60% sodium hydride in oil (80 mg) is dispersed in 5 ml of dimethylformamide and 582 mg of 4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) - 1,2,4-triazolone is added under ice cooling. The mixture was stirred at room temperature for 10 minutes. 474 mg of (2RS) -2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) methyloxyran (synthesized according to the method of Japanese patent Laid-Open Sho 58-32868) was added to the mixture. ) and the resulting mixture is heated at 60 ^° C. for 15 minutes. After cooling, the reaction solution was fractionated by adding 20 ml of cold water and 40 ml of ethyl acetate, and the cooled aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane: acetone = 2: 1) to obtain 510 mg of 2 - [(2RS) -2- (2,4-difluorophenyl) -2-hydroxy-3- (1H-1, 2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 54) in the form of a white powder.

¹ H-NMR (CDCl ₃ ) δ: 4.18 (1H, d, J = 15 Hz), 4.40 (2H, t, J = 12 Hz), 4.61 (1H, d, J = 15 Hz ), 4.71 (2H, s), 5.80 (1H, s), 6.05 (1H, tt, J = 5.2, 54 Hz), 6.77-6.87 (2H, m) 7.01 (2H, d, J = 8.6 Hz), 7.37 (2H, d, J = 8.6 Hz), 7.53 (1H, s), 7.56-7.64 ( 1H, m), 7.84 (1H, s), 8.15 (1H, s). Mp 79-80 ^o C.

 Working Example 52. 60% sodium hydride in oil (40 mg) is dispersed in 4 ml of dimethylformamide and 250 mg of 2- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone is added under ice cooling . The mixture was stirred at room temperature for 10 minutes.

 237 mg of (2RS) -2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) methyloxirane was added to the mixture, and the resulting mixture was stirred at room temperature for 22 hours. After after cooling, the reaction solution was fractionated by adding 15 ml of cold water and 30 ml of ethyl acetate, and the separated aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent, ethyl acetate: hexane = 3: 1 to ethyl acetate) to obtain 92 mg of 4 - [(2RS) -2- (2,4-difluorophenyl) -2-hydroxy-3- (1H -1,2,4-triazol-1-yl) propyl] - 2- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 55) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 4.20 (2H, s), 4.51 (1H, d, J = 14.4 Hz), 4.80 (1H, d, J = 14.4 Hz) 5.93 (1H, s), 6.80-6.89 (2H, m), 7.31 (2H, d, J = 9.2 Hz), 7.51-7.59 (1H, m ), 7.61 (1H, s), 7.87 (1H, s), 7.92 (2H, d, J = 9.2 Hz), 8.05 (1H, s).

Mp 128-130 ^o C.

 Working example 53. By the same method as in working example 51, starting from 0.19 g of (2RS) -2- (2,4-difluorophenyl) -2- (1-indidazolyl) methyloxyran and 0.23 g of 4- [4 - (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone get 2 - [(2RS) -2- (2,4-difluorophenyl) -2-hydroxy -3- (1-imidazolyl) propyl] - 4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 56: 0, 23 g) as a colorless powder. Yield 55%.

¹ H-NMR (CDCl ₃ ) δ: 4.20 (1H, d, J = 15 Hz), 4.37 (2H, s), 4.37 (2H, t, J = 12 Hz), 4.57 (1H, d, J = 15 Hz), 5.76 (1H, s), 6.04 (1H, tt, J = 5.2 Hz, 54 Hz), 6.75-6.98 (2H, m ), 6.92 (1H, s), 7.00 (2H, d, J = 9.2 Hz), 7.26 (1H, s), 7.35 (2H, d, J = 9.2 Hz ), 7.43-7.60 (1H, m), 7.45 (1H, s), 7.51 (1H, s).

 Working example 54. By the same method as in working example 51, starting from 0.24 g of (2RS) -2- (2,4-difluorophenyl) -2- (1H-1,2,4-tetrazolyl-1-yl) methyloxiran and 0.28 g of 4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone get 2 - [(2R) -2- ( 2,4-difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 78: 0.22 g) as a colorless powder. Yield 43%.

¹ H-NMR (CDCl ₃ ) δ: 4.19 (1H, d, J = 15 Hz), 4.61 (1H, q, J = 15 Hz), 4.72 (2H, s), 5.71 (1H, s), 5.92 (1H, tt, J = 2.8 Hz, 53 Hz), 6.76-6.88 (2H, m), 7.31 (2H, d, J = 10 Hz ), 7.46-7.64 (1H, m), 7.49 (2H, d, J = 10 Hz), 7.59 (1H, s), 7.84 (1H, s), 8.14 (1H, s).

 Working examples 55-61. The following compounds were obtained in accordance with the method described in working example 54.

 Working Example 55. 2 - [(2R) -2- (2,4-Difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triaeol-1-yl) propyl] -4- [4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 90), colorless powder. Yield 30%.

¹ H-NMR (CDCl ₃ ) δ: 4.18 (1H, d, J = 15 Hz), 4.37 (2H, q, J = 8 Hz), 4.60 (1H, d, J = 15 Hz ), 4.71 (2H, s), 5.79 (1H, s), 6.77-6.98 (2H, m), 7.02 (2H, d, J = 10 Hz), 7.37 (2H, d, J = 10 Hz), 7.46-7.64 (1H, m), 7.53 (1H, s), 7.84 (1H, s), 8.15 (1H, s) .

 Working Example 56. 2 - [(2R) -2- (2,4-Difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 94), colorless powder. Yield 31%.

¹ H-NMR (CDCl ₃ ) δ: 4.18 (1H, d, J = 15 Hz), 4.44 (2H, t, J = 12 Hz), 4.60 (1H, d, J = 15 Hz ), 4.71 (2H, s), 5.79 (1H, s), 6.77-6.86 (2H, m), 7.02 (2H, d, J = 8.8 Hz), 7 , 38 (2H, d, J = 8.8 Hz), 7.53 (1H, s), 7.56-7.64 (1H, m), 7.84 (1H, s), 8.15 ( 1H, s).

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ +13.5 (C = 1.0, methanol)
Working Example 57. 4 - [(2S) -2- (2,4-Difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl] -2- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 75), colorless powder. Yield 20%.

¹ H-NMR (CDCl ₃ ) δ: 4.14 (1H, d, J = 15 Hz), 4.24 (1H, d, J = 15 Hz), 4.32 (2H, t, J = 12 Hz ), 4.51 (1H, d, J = 15 Hz), 4.77 (1H, d, J = 15 Hz), 6.02 (1H, s), 6.06 (1H, tt, J = 4 , 8 Hz, 54 Hz), 6.71-6.98 (2H, d, J = 9.2 Hz), 7.03 (2H, d, J = 9.2 Hz), 7.51-7.63 (1H, m), 7.55 (1H, s), 7.79 (2H, d, J = 9.2 Hz), 7.86 (1H, s), 8.06 (1H, s).

 Working Example 58. 4 - [(2S) -2- (2,4-Difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl] -2- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3- (2H, 4H) -1,2,4-triazolone (compound 79), colorless powder. Yield 23%.

¹ H-NMR (CDCl ₃ ) δ: 4.15 (1H, d, J = 14 Hz), 4.24 (1H, d, J = 14 Hz), 4.50 (1H, d, J = 14 Hz ), 4.79 (1H, d, J = 14 Hz), 5.92 (1H, tt, J = 2.8 Hz, 53 Hz), 5.94 (1H, s), 6.79-6, 88 (2H, m), 7.25 (2H, d, J = 10 Hz), 7.50-7.62 (1H, m), 7.59 (1H, s), 7.87 (1H, s ), 7.91 (2H, d, J = 10 Hz), 8.05 (1H, s).

[α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ -12.4 ^o (C = 1.0, methanol)
Working Example 59. 4 - [(2S) -2- (2,4-Difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl] -2- [4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazole (compound 91), colorless powder. Yield 22%.

¹ H-NMR (CDCl ₃ ) δ: 4.14 (1H, d, J = 14 Hz), 4.24 (1H, d, J = 14 Hz), 4.35 (2H, q, J = 8 Hz ), 4.51 (1H, d, J = 14 Hz), 4.76 (1H, d, J = 14 Hz), 6.02 (1H, s), 6.72-6.89 (2H, m ), 6.97 (2H, d, J = 9.2 Hz), 7.51-7.63 (1H, m), 7.55 (1H, s), 7.79 (2H, d, J = 9.2 Hz), 7.86 (1H, s), 8.06 (1H, s).

 Working Example 60. 2 - [(2R) -2- (2,4-Difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 74), colorless powder. Yield 46%.

¹ H-NMR (CDCl ₃ ) δ: 4.18 (1H, d, J = 15 Hz), 4.40 (2H, t, J = 12 Hz), 4.61 (1H, d, J = 15 Hz ), 4.71 (2H, s), 5.80 (1H, s), 6.05 (1H, tt, J = 5.2 z, 54 Hz), 6.77-6.87 (2H, m ), 7.01 (2H, d, J = 8.6 Hz), 7.37 (2H, d, J = 8.6 Hz), 7.53 (1H, s), 7.56-7.64 (1H, m), 7.84 (1H, s), 8.15 (1H, s).

 Working Example 61. 2 - [(2R) -2- (2,4-Difluorophenyl) -2-hydroxy-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4- trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 70), colorless powder. Yield 41%.

¹ H-NMR (CDCl ₃ ) δ: 4.19 (1H, d, J = 15 Hz), 4.60 (1H, d, J = 15 Hz), 4.72 (2H, s), 5.69 (1H, s), 6.76-6.88 (2H, m), 7.32 (2H, d, J = 9 Hz), 7.46-7.64 (1H, m), 7.50 ( 2H, d, J = 9 Hz), 7.59 (1H, s), 7.84 (1H, s), 8.14 (1H, s).

 Working examples 62-71. The following compounds were obtained in accordance with the method described in working example 2.

 Working Example 62. 1-1 [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl ] -3- [4- [4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] - 1-piperisinyl] phenyl] -2 (1H, 3H) -imidazolone (compound 104), colorless powder. Yield 62%.

¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 7 Hz), 3.23-3.38 (8H, m), 4.22 (1H, d, J = 15 Hz) , 4.31 (2H, t, J = 12 Hz), 4.92 (1H, q, J = 7 Hz), 5.10 (1H, d, J = 15 Hz), 6.08 (1H, tt , J = 53.5 Hz), 6.59 (1H, d, J = 3.0 Hz), 6.68 (1H, d, J = 3.0 Hz), 6.73-7.06 (8H , m), 7.43-7.54 (3H, m), 7.72 (1H, s), 7.89 (1H, s).

 Working Example 63. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- [4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] - 1-piperazinyl] phenyl] -3 (2H, 4H) -1,2,4-triazolone (compound 105 ), colorless powder. Yield 54%.

¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 7.0 Hz), 3.23-3.42 (8H, m), 4.31 (2H, t, J = 12 Hz), 4.35 (1H, d, J = 15 Hz), 5.02 (1H, d, J = 15 Hz), 5.09 (1H, q, J = 7.0 Hz), 5.58 (1H, s), 6.07 (1H, tt, J = 53, 5.0 Hz), 6.76-7.00 (6H, m), 7.06 (2H, d, J = 9 Hz) 7.43 (2H, d, J = 9 Hz), 7.50-7.62 (1H, m), 7.68 (1H, s), 7.73 (1H, s), 7.96 ( 1H, s).

 Working Example 64. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,2-trifluoroethoxy) phenyl] -5 (1H, 4H) -1,2,4-triazolone (compound 106), colorless powder. Yield 27%.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7 Hz), 4.35 (1H, d, J = 16 Hz), 4.41 (2H, q, J = 8 Hz ), 5.08 (1H, d, J = 16 Hz), 5.10 (1H, q, J = 7 Hz), 5.51 (1H, s), 6.75-6.88 (2H, m ), 7.09 (2H, d, J = 9 Hz), 7.51-7.63 (1H, m), 7.72 (1H, s), 7.90 (2H, d, J = 9 Hz ), 7.91 (1H, s).

 Working Example 65. 1- [1 (1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl ] -4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] - 5 (1H, 4H) -1,2,4-triazole (compound 107), a colorless powder. Yield 48%.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7.2 Hz), 4.34 (1H, d, J = 14.4 Hz), 5.08 (1H, d, J = 14.4 Hz), 5.10 (1H, q, J = 7.2 Hz), 5.50 (1H, s), 5.95 (1H, tt, J = 52.8, 2.8 Hz), 6.73-6.91 (2H, m), 7.38 (2H, d, J = 9 Hz), 7.49-7.64 (1H, m), 7.72 (1H, s ), 7.91 (1H, s), 8.01 (2H, d, J = 9 Hz).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3400, 3080, 1730, 1618, 1514, 1502, 1387.

 Working Example 66. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] - 5 (1H, 4H) -1,2,4-triazolone (compound 108), a colorless powder. Yield 53%.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, d, J = 7.2 Hz), 4.35 (1H, d, J = 14.2 Hz), 4.47 (2H, dt, J = 12.2, 1 Hz), 5.08 (1H, d, J = 14.2 Hz), 5.10 (1H, q, J = 7.2 Hz), 5.50 (1H, s) 6.74-6.90 (2H, m), 7.09 (2H, d, J = 9.2 Hz), 7.49-7.65 (1H, m), 7.72 (1H, s ), 7.90 (2H, d, J = 9.2 Hz), 7.91 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 3400, 3080, 1726, 1618, 1599, 1516, 1460.

 Working Example 67. 1 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3,4,4,5,5-octafluoropentoxy) phenyl] -5 (1H, 4H) -1,2,4-triazolone (compound 109), colorless powder. Yield 42%.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 7.2 Hz), 4.35 (1H, d, J = 14.4 Hz), 4.53 (2H, t, J = 13 Hz), 5.08 (1H, d, J = 14.4 Hz), 5.10 (1H, q, J = 7.2 Hz), 5.52 (1H, s), 6.11 (1H, tt, J = 52, 5.4 Hz), 6.74-6.91 (2H, m), 7.10 (2H, d, J = 9.2 Hz), 7.50-7, 66 (1H, m), 7.73 (1H, s), 7.91 (2H, d, J = 9.2 Hz), 7.92 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 ; 3400, 3080, 1722, 1618, 1599, 1516, 1459.

 Working Example 68. 2 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -5-methyl-4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -l, 2,4-triazole (compound 110), colorless powder. Yield 44%.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, d, J = 7 Hz), 2.19 (3H, s), 4.40 (1H, d, J = 14.8 Hz), 4 42 (2H, t, J = 11.8 Hz), 4.97 (1H, d, J = 14.8 Hz), 5.06 (1H, q, J = 7 Hz), 5.62 (1H , s), 6.08 (1H, tt, J = 53.2 Hz, J = 4.6 Hz), 6.84-6.90 (2H, m), 7.09 (2H, dt, J = 9 Hz, 2.6 Hz), 7.33 (2H, dt, J = 9 Hz, 2.6 Hz), 7.50-7.65 (1H, m), 7.70 (1H, s), 7.98 (1H, s).

 Working Example 69. 2- [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3 (1H-1,2,4-triazol-1-yl) propyl] - 5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] - 3 (2H, 4H) -1,2,4-triazolone (compound 111), a colorless powder. Yield 46%.

¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, d, J = 7 Hz), 2.24 (3H, s), 4.42 (1H, d, J = 14.6 Hz), 4 98 (1H, d, J = 14.6 Hz), 5.07 (1H, q, J = 7 Hz), 5.55 (1H, s), 5 96 (1H, tt, J = 53.2 Hz, 2.8 Hz), 6.75-6.90 (2H, m), 7.41 (4H, s), 7.50-7.65 (1H, m), 7.71 (1H, s ), 7.97 (1H, s).

 Working Example 70. 2- (4-Chlorophenyl) -4 - [(1R, 3R) -2- (2,4-difluorophenyl) - 2-hydroxy-1-methyl-3- (1H-1,2,4- triazol-1-yl) propyl] -5-methyl-3 (2H, 4H) -1,2,4-triazolone (compound 112), a colorless powder. Yield 77%.

¹ H-NMR (400 MHz, DMSO-d ₆ , 138 ^o C) δ: 1.33 (3H, d, J = 7 Hz), 2.38 (3H, s), 4.49 (1H, d, J = 14.2 Hz), 4.76-4.90 (1H, m), 4.89 (1H, d, J = 14.2 Hz), 6.23 (1H, br), 6.88- 6.95 (1H, m), 6.99-7.07 (1H, m), 7.46-7.54 (1H, m), 7.46 (2H, d, J = 9 Hz), 7 55 (1H, s), 7.90 (2H, d, J = 9 Hz), 8.14 (1H, s).

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 1712, 1702, 1680, 1650, 1619, 1502.

 Working Example 71. 4 - [(1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -5-methyl-2- (4-trifluoromethoxyphenyl) - 3 (2H, 4H) -tetrazolone (compound 113), a colorless powder. Yield 72%.

IRυ $\genfrac{}{}{0ex}{}{\text{KBr}}{\text{max}}$ cm ^-1 : 1700, 1678, 1610, 1508, 1256, 1220.

Working Example 72. A mixture of 60% (w / w) sodium hydride in oil (10 mg) and dimethylformamide (2 ml) was added 4- (4-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4 triazolone (59 mg) at 0 ^° C. The resulting mixture was stirred at room temperature for 10 minutes. (2R, 2S) -2- (2,4-difluorophenyl) -3-methyl-2 - [(1H-1,2,4-triazol-1-yl) methyl] oxirane (63 mg) was added to the mixture. After stirring for 19 hours at 70 ^° C., the mixture was diluted with water (4 ml) and extracted with ethyl acetate (4 ml x 2). The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent, ethyl acetate: hexane = 3: 1 to ethyl acetate) to obtain 1 - [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl- 3- (1H- 1,2,4-triazol-1-yl) propyl] -4- (4-trifluoromethylphenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 10) as a colorless powder (10 mg).

 Working Example 73. By the same method as in Working Example 72, (2R, 2S) -2- (2,4-difluorophenyl) -3-methyl-2 - [(1H-1,2,4-triazole-1- il) methyl-oxiran (63 mg) is reacted with 2- (4-trifluoromethylphenyl) -3 (2H, 4H) - 1,2,4-triazolone (59 mg) to give 4 - [(1R, 2R) -2 - (2,4-difluorophenyl) - 2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- (4-trifluoromethylphenyl) - 3 (2H, 4H ) -1,2,4-triazolone (compound 11) as a white powder (12 mg).

 Working Example 74. By the same method as in Working Example 72, (2R, 3S) -2- (2,4-difluorophenyl) -3-methoxy-2 - [(1H-1,2,4-triazole-1- il) methyl] -oxyran (251 mg) was reacted with 2- (4-fluorophenyl) -3 (2H, 4H) -1,2,4-triazolone (358 mg) to give 4 - [(1R, 2R) - 2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- (4-fluorophenyl) -3 (2H, 4H) -1,2,4-triazolone (compound 15) as a white powder (76 mg).

 Working example 75. By the same method as in working example 72, (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2 - [(1H-1,2,4-triazole-1- il) methyl] -oxyran (251 mg) is reacted with 2- (4-chlorophenyl) -3 (2H, 4H) -1,2,4-triazolone (392 mg) to give 2- (4-chlorophenyl) -4 - [(1R, 2R) -2- (2,4-difluorophenyl) - 2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3 (2H, 4H) -1,2,4-triazolone (compound 35) as colorless prisms (48 mg).

 A preferred group of compounds expressed by a compound of general formula I according to the invention is illustrated in table. 8-27, which, however, does not limit the invention to the compounds represented therein.

 Cooking 1.

 Using the compound 30 obtained in working example 27, the following components are mixed. The mixture is packaged in gelatin capsules to obtain capsules, each of which contains compound 30 in an amount of 50 mg.

Compound 30 (obtained in working example 27) - 50 mg
Lactose - 100 mg
Corn Starch - 40 mg
Magnesium Stearate - 10 mg
Total - 200 mg
Cooking 2.

 Compound 35 obtained in working example 32 and magnesium stearate are granulated in a soluble starch solution. The resulting product is dried and then mixed with lactose and corn starch. The mixture is pressed to obtain a tablet containing these components.

Compound 35 (obtained in working example 32 to 50 mg
Lactose - 65 mg
Corn Starch - 30 mg
Soluble Starch - 35 mg
Magnesium Stearate - 20 mg
Total - 200 mg
Evaluation of the antifungal activity of the compounds of formula I was carried out according to the following procedure: a sheet of filter paper (manufactured by Toyo Seisakusho, 8 mm in diameter), impregnated with a 1000 mg / ml solution of the compound of formula I in methanol, was placed on an agar plate containing various fungi, incubated at 28 ^o C for two days and then measured the diameter of the growth of the inhibited zone around the filter paper. The following culture media were used:
A: Nitrogen-basic yeast agar medium (pH 7.0)
B: peptone-yeast extract-glucose agar medium (pH 7.0).

 The antifungal activity of the compounds of formula I is shown in table. 28.

 The antifungicidal activity of the compound of formula I against Candida albicans is shown in table. 29-32.

 The protective properties of the compounds of formula I against Candida albicans infection are shown in mice and are shown in table. 33 and 34.

Research Method: Five-week-old Crj: CDF ₁ mice were vaccinated with a minimum lethal dose of Candida albicans intravenously. The test compound was administered orally once, immediately after infection. Activity is expressed in units of ED ₅₀ calculated by the method of Reed and Muench for the degree of survival after 7 days after infection.

Claims (29)

1. The azole derivative of the formula I

where Ar is a phenyl group disubstituted by halogen;
R ¹ is a hydrogen atom or a lower alkyl group;
R ³ is lower alkyl, possibly substituted by halogen, phenyl, unsubstituted or substituted by lower alkyl, halogen, trifluoromethyl, lower alkoxy, halo (lower) alkoxy, piperazinyl, benzylpiperazinyl, lower acylpiperazinyl, lower alkoxyphenylphenylpiperazene, or pyrimidinyl radical;
X is a nitrogen atom or a methine group;
Y and Z, independently, are a nitrogen atom or a methine group, which optionally can be further substituted with a lower alkyl group,
or its acid addition salts.  2. The compound or its salt according to claim 1, where X is a nitrogen atom. 3. The compound or its salt according to claim 1, where R ¹ is methyl.  4. The compound or its salt according to claim 1, where Ar is a 2,4-difluorophenyl group. 5. The compound or its salt according to claim 1, where R ³ is phenyl unsubstituted or substituted by lower alkyl, halogen, trifluoromethyl, lower alkoxy, halogen (lower) alkoxy, piperazinyl, benzyl piperazinyl, lower acyl piperazinyl, lower alkoxyphenyl alkyl piperazine, may be substituted by halogen. 6. The compound or its salt according to claim 1, where R ³ is a substituted phenyl group. 7. The compound or its salt according to claim 6, where R ³ is a phenyl group which is substituted by a halogen atom. 8. The compound or its salt according to claim 6, where R ³ is a phenyl group which is substituted with a trifluoromethyl group. 9. The compound or its salt according to claim 6, where R ³ is a phenyl group substituted by a halogen (lower) alkoxy group. 10. The compound or its salt according to claim 7, where R ³ - 4-chlorophenyl. 11. The compound or its salt of claim 8, where R ³ - 4-trifluoromethylphenyl. 12. The compound or its salt according to claim 9, where R ³ - 4-trifluoromethoxyphenyl. 13. The compound or its salt according to claim 9, where R ³ is 4- (2,2,2-trifluoroethoxy) phenyl. 14. The compound or its salt according to claim 9, where R ³ - 4- (2,2,3,3-tetrafluoropropoxy) phenyl. 15. The compound or its salt according to claim 9, where R ³ - 4- (1,1,2,2-tetrafluoroethoxy) phenyl. 16. The compound or its salt according to claim 9, where R ³ - 4- (2,2,3,3,3-pentafluoropropoxy) phenyl.  17. The compound or its salt according to claim 1, where Y and Z, independently, are a hydrogen atom or a methine group, which may be optionally substituted with a methyl group.  18. The compound or its salt according to claim 1, where any of Y and Z is a nitrogen atom and the other is a methine group.  19. The compound according to claim 1, which is 2 - [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole- 1-yl) propyl] -4- (4-trifluoromethoxyphenyl) -3- (2H, 4H) -1,2,4-triazolone or a salt thereof.  20. The compound according to claim 1, representing 2 - [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole- 1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone or a salt thereof.  21. The compound according to claim 1, which represents 2 - [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole- 1-yl) propyl] -4- [1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2-4-triazolone or its salt.  22. The compound according to claim 1, which is 4 - [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H, 1,2,4-triazole- 1-yl) propyl] -2- (4-trifluoromethoxyphenyl) -3 (2H, 4H) -1,2,4-tetrazolone or a salt thereof.  23. The compound according to claim 1, representing 2 - [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole- 1-yl) propyl] -4- [4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2-4-triazolone or a salt thereof.  24. The compound according to claim 1, which is 4 - [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole- 1-yl) propyl] -4- [4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2, -4-triazolone or its salt.  25. The compound according to claim 1, which is 4 - [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole- 1-yl) propyl] -2- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone or a salt thereof.  26. The compound according to claim 1, which represents 2 - [(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole- 1-yl) propyl] -4- [4- [4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl-1-piperazinyl] phenyl] -3- (2H, 4H) -1.2, 4-triazolone or its salt. 27. The method of obtaining the compounds of formula I or its salts according to claim 1, characterized in that they carry out the reaction of the compounds represented by formula II:

where the values of the radicals are the same as indicated for formula I,
with the compound represented by formula III

where the values of the radicals are the same as indicated for formula I,
or its salt. 28. The method of obtaining the compounds of formula I or its salts according to claim 1, characterized in that they carry out the reaction of the compounds represented by formula IV

where the values of the radicals are the same as indicated for formula I,
or its salt with a compound represented by formula V

where the values of the radicals are the same as indicated for formula I,
or with its salt.  29. A pharmaceutical composition exhibiting antifungal activity containing an azole derivative as an active compound and a pharmaceutically acceptable carrier, excipient or diluent, characterized in that the azole derivative contains an effective amount of a compound represented by formula I as described in claim 1, or a pharmaceutically acceptable salt thereof.

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