JP2630877B2 - Optically active triazole derivatives and compositions - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the following formula ((+)-I) having antifungal activity and useful for treating fungal infections in humans and other animals.

[0002]

Embedded image (In the formula, * indicates optical activity) (+)-2- (2,4-difluorophenyl) -1-
[3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] -3- (1H-1,2,2,3 4-triazol-1-yl) propan-2-ol, pharmaceutically acceptable salts thereof, solvates thereof and solvates of the salts,
And a method for producing the same, and a pharmaceutical composition comprising the same as an active ingredient. The present invention also relates to an intermediate for producing the compound represented by the formula ((+)-I) and a production method thereof.

[0003]

2. Description of the Related Art The following equation ((±) -I)

[0004]

Embedded image 2- (2,4-difluorophenyl) -1- represented by
[3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] -3- (1H-1,2,2,3 4-Triazol-1-yl) propan-2-ol (hereinafter referred to as compound A) is known to have extremely high antifungal activity (Y. H., Song et al. (YH.
Thong et al . ), Journal of
Anti-micro vial Chemotherapy (Journal
of Antimicrobial Chemoth
erapy), 21, 755-763, 1988.
Year). Compound A has an asymmetric carbon in the molecule, but has been treated as a racemate since the structure was disclosed in European Patent 0177469. However, as can be seen from the lesson from the thalidomide case, in a compound having an asymmetric carbon, even if one of the optically active compounds is a useful compound, the racemic form or the other optically active compound is not expected. May be toxic. It is also known that one optically active substance is superior in pharmacological activity to the other optically active substance, or has different pharmacokinetics. From this point of view, when developing a racemic form of a compound having an asymmetric carbon as a drug today, it is necessary to submit detailed knowledge not only of the racemic form but also of the pharmacological activity, toxicity and pharmacokinetics of each optically active form. Is being sought.

The present inventors have conducted a pharmacological test on Compound A, and as a result, have confirmed that Compound A certainly has strong antifungal activity. Further, the present inventors investigated the toxicity of compound A by continuously administering it to monkeys.
At a dose of 3 mg / kg / day or more, a serum cortisol-lowering effect (histologically, mild to intense hyperplasia of the adrenocortical bundle and an increase in lipid droplets) and tubule atrophy of the testis,
It was confirmed that a dose of 30 mg / kg / day had side effects such as an effect of prolonging the QTc time on the electrocardiogram (meaning a delay in repolarization and a risk of inducing severe arrhythmia). Furthermore, from the change in plasma concentration, compound A
It was found to show accumulation.

[0006] Therefore, how to make this compound a highly safe drug in order to actually develop this compound as a drug has been raised as a major issue.

[0007]

Means for Solving the Problems The present inventors have prepared a compound A
Focusing on the fact that is a racemic form, I came up with the idea of first examining the toxicity, pharmacological activity, etc. of each of the optically active forms as a clue to solving the problem. However, the optically active form of Compound A has never been isolated and produced, and its physicochemical or pharmacological properties have not been known at all.

Therefore, the present inventors focused on the asymmetric carbon of Compound A and conducted intensive research on the asymmetric synthesis of an optically active form of Compound A. As a result, first, the following formula (II)

[0009]

Embedded image (In the formula, * represents optical activity, and A and A ′
And A together represent an oxygen atom, or A 'represents a hydroxyl group, A represents a hydroxyl group, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and R represents a hydroxyl group, an acetoxy group, 1H-1,2,4-triazo. -Yl-1-yl group or 3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl group; (A and R are not hydroxyl groups at the same time.) (-)-Or (+)-2-
The (2,4-difluorophenyl) -propane derivative was successfully synthesized stereoselectively. Next, both of the optically active compounds (-) and (+) can be used as an intermediate for producing the compound of the present invention represented by the formula ((+)-I), and the compound is industrially used by using the compound It has been found that the compound of the present invention ((+)-I) can be produced.

In the specification of the present invention, the optically active compounds described in the (+)-form or the (-)-form refer to (+) or (-) with respect to the D line of sodium, respectively. ), Which are optically active, and have an enantiomeric relationship with each other. Further, hereinafter, regarding the expression of the compound in the specification of the present invention, the expression with the compound represented by the formula (N) is also expressed as a compound N (N is a Roman numeral I to XX).
Corresponding to).

Thus, each optically active form of compound A was synthesized, and first, the (+)-form (compound (+)-
As a result of examining the antifungal activity of the (I) and the (-)-form (compound (-)-I), the compound (+)-I was converted to the compound (-)-
It was found that the antifungal activity was remarkably stronger than that of I. Next, compound (+)-I was continuously administered to monkeys to examine its toxicity.

As a result, the compound (+)-I was 10 m
g / kg / day showed slight hyperplasia of the adrenal cortex and increased lipid droplets at a dose of 30 mg / kg / day.
At doses of y, there was no cardiotoxicity (extended QTc time), testicular toxicity (tubule atrophy) and serum cortisol-lowering effects, and we have found that compound (+)-I has antifungal activity and side effects. I discovered that it was dissociating brilliantly. In addition, the change in plasma concentration revealed that compound (+)-I also did not show accumulation. Therefore, compound (+)-I
Was confirmed to be a safe and useful antifungal agent.

In order to clearly separate the side effect and pharmacological action of Compound A from the above results, the (+) optically active compound (Compound (+)-I) is synthesized stereoselectively, and We understand that we need to further develop it as a pharmaceutical,
The present invention has been completed.

The compound (+)-I of the present invention can form a salt with a pharmaceutically acceptable inorganic or organic acid. Examples of these salts include salts with inorganic acids such as hydrochloride, sulfate, and nitrate; salts with organic acids such as acetate, p-toluenesulfonate, methanesulfonate, and maleate; and lysine. Salts and amino acid salts such as arginine salts. The salt is mixed in a customary manner, for example by mixing an equimolar amount of the free compound (+)-I with a solution containing the desired acid and collecting the desired salt by filtration (if insoluble) or solvent evaporation.

The production of the intermediate of the present invention and the production of the compound (+)-I of the present invention using the intermediate as a starting material can be carried out, for example, according to the following reaction formula.

[0016]

Embedded image Step 1 in the above reaction scheme involves condensing 2,4-difluorobromobenzene (III) with 1,3-dichloroacetone, and is a method known in the literature (for example,
For example, the reaction is carried out in the presence of a base such as n-butyllithium in an organic solvent such as anhydrous ether or hexane. Step 2 is a step of closing a ring to an epoxide. For example, the reaction is carried out in an organic solvent such as dimethylformamide in the presence of a base such as sodium hydride. Step 3 is a step of synthesizing allyl alcohol. In this step, a reducing agent such as sodium hydroxymethanesulfinate, sodium borohydride, lithium triethylborohydride is allowed to act on tellurium in the presence of a base such as sodium hydroxide to generate telluride ions in the reaction system. Thereafter, this is carried out by reacting this with 1-chloro-2- (2,4-difluorophenyl) -2,3-epoxypropane (V).
In this step, selenium can be used instead of tellurium. This step can also be carried out by reducing compound V with zinc or the like in an organic solvent such as dimethylformamide. Step 4 is an asymmetric oxidation step.
2- (2,4-difluorophenyl) allyl alcohol (VI) is dissolved in an organic solvent such as methylene chloride in a titanium tetraalkoxide such as titanium tetraisopropoxide and titanium tetrabutoxide and diethyl (+)-tartrate;
In the presence of (+)-dialkyl tartrate such as (+)-diisopropyl tartrate, (+)-dicyclohexyl tartrate, t
Oxidation with -butyl hydroperoxide gives (-)-2- (2,4-difluorophenyl) -2,3
-Epoxypropanol ((-)-VII) can be obtained with high optical purity. In this step, (+)
When (−)-dialkyl tartrate is used instead of dialkyl tartrate, (+)-2- (2,4-difluorophenyl) -2,3-epoxypropanol ((+)
-VII) is obtained with high optical purity.

Compound VI can also be produced as follows. That is, by reacting compound IV with a Grignard reagent such as ethylmagnesium bromide in an organic solvent such as ether in the presence of ferric chloride or the like, 1-
(2,4-Difluorophenyl) -cyclopropanol was obtained, and then the hydroxyl group was converted to a sulfonic ester using methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base such as triethylamine, and this was converted to a base such as calcium carbonate. To give compound VI. Compound VI can also be produced as follows. That is, 2,4-difluorobenzophenone is reacted with a methylation reagent such as trimethylsulfoxonium iodide in the presence of a base such as sodium hydride to give 2- (2,4-difluorophenyl) -1,2.
-After synthesizing epoxypropane, compound VI can also be obtained by reacting it with iodotrimethylsilane in the presence of a base such as 1,8-diazabicyclo [5,4,0] -7-undecene.

The optically active compound VII can also be produced according to the following reaction formula.

[0019]

Embedded image Step A is a ring opening reaction of the epoxide, which is carried out by reacting compound V with sodium acetate in an organic solvent such as acetic acid. Step B is a step of re-closing the epoxide. For example, the reaction is carried out in the presence of a base such as sodium hydride in an organic solvent such as dimethoxyethane. Step c is an asymmetric hydrolysis step of an ester by an enzyme, in which a hydrolytic enzyme such as esterase or lipase is dissolved in a buffer or a mixed solvent of the buffer and an organic solvent such as diisopropyl ether, ethanol, acetone, and dimethylformamide. It is performed using. In this step, the (+)-form is selectively subjected to ester hydrolysis,
(+)-2- (2,4-difluorophenyl) -2,3
-Epoxypropanol ((+)-VII) is obtained. On the other hand, (-)-1-acetoxy-2- (2,4-difluorophenyl) -2,3-epoxypropane ((-)
-IX) is not subject to ester hydrolysis and is recovered from the reaction solution with high optical purity. Step d is the usual ester hydrolysis, and the compound (-)-IX recovered in step c
Is hydrolyzed with a base such as potassium hydroxide or sodium hydroxide to give (-)-2- (2,4-difluorophenyl) -2,3-epoxypropanol ((-)-V
II) is obtained.

[0020]

Embedded image Step 5 in the above reaction formula is a step of condensing triazole. By reacting compound (-)-VII with 1,2,4-triazole in an organic solvent such as tetrahydrofuran or dimethylformamide in the presence of a base such as potassium carbonate, potassium hydrogen carbonate or sodium hydride, (-)- 2- (2,4-difluorophenyl) -3-
(1H-1,2,4-triazol-1-yl) propane-1,2-diol ((-)-X) can be obtained. The present compound can be obtained as an optically pure compound by recrystallization from an organic solvent such as chloroform. Step 6 is a step of closing a ring to an epoxide.
First, in an organic solvent such as ether and tetrahydrofuran,
By reacting with methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of an excess amount of a base such as triethylamine or pyridine to convert a primary hydroxyl group to a sulfonic ester, and then treating this reaction solution with water, Epoxidized by the action of the base present in excess,
(+)-2- (2,4-difluorophenyl) -3-
(1H-1,2,4-triazol-1-yl) -2,
3-epoxypropane ((+)-XI) can be obtained. In this step, it is possible to isolate the sulfonic acid ester, but it is preferable to perform the isolation without isolation in operation. Step 7 is a step of condensing the substituted triazole. The compound (+)-XI is known per se in an organic solvent such as tetrahydrofuran, dimethylformamide, ethanol or the like in the presence of a base such as potassium carbonate, potassium hydrogen carbonate, sodium hydride or the like (for example, JP-A-61-61).
72767) Compound 3-[(E) -4- (2,
2,3,3-tetrafluoropropoxy) styryl]-
By reacting with 1H-1,2,4-triazole (XII), (+)-2- (2,4-difluorophenyl) -1- [3-[(E) -4- (2,2,3 , 3-Tetrafluoropropoxy) styryl] -1H-1,2,2
4-triazol-1-yl] -3- (1H-1,2,2
4-Triazol-1-yl) propan-2-ol ((+)-I) can be obtained. The present compound can be obtained as an optically pure compound by recrystallization from an organic solvent such as ethyl acetate, ether, hexane or a mixed solvent thereof.

In this production method, even when compound (+)-VII is used instead of compound (-)-VII as a raw material, the introduction order of 1,2,4-triazole and substituted triazole (XII) is changed. Thereby, compound (+)-I can be obtained. That is, compound (+)-I can also be produced according to the following reaction formula.

[0022]

Embedded image Step 5 ′ is a step of condensing the substituted triazole.
Compound (+)-VII was prepared in an organic solvent such as tetrahydrofuran or dimethylformamide in the presence of a base such as potassium carbonate, potassium hydrogen carbonate or sodium hydride.
[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazole to give (+)-2- (2,4-difluorophenyl ) -3- (1H-1,2,4-triazol-1-yl) propane-1,2-diol ((+)-
XIII) can be obtained. Step 6 ′ is a step of closing the ring to the epoxide. First, methanesulfonyl chloride or p-toluenesulfonyl chloride is reacted in an organic solvent such as ether, tetrahydrofuran or dimethylformamide in the presence of a base such as triethylamine or pyridine to convert a primary hydroxyl group to a sulfonic acid ester. The obtained sulfonic acid ester is epoxidized using a base such as sodium hydride to give (−)-2- (2,4-
Difluorophenyl) -3- (1H-1,2,4-triazol-1-yl) -2,3-epoxypropane ((-)-XIV) can be obtained. In this step, it is also possible to isolate the sulfonic acid ester.
Step 7 'is a step of condensing the triazole. Compound (-)-XIV was converted to 1,2,4 in an organic solvent such as tetrahydrofuran or dimethylformamide in the presence of a base such as potassium carbonate, potassium hydrogen carbonate or sodium hydride.
-(+)-2- by reacting with triazole
(2,4-difluorophenyl) -1- [3-[(E)
-4- (2,2,3,3-tetrafluoropropoxy)
[Styryl] -1H-1,2,4-triazol-1-yl] -3- (1H-1,2,4-triazol-1-yl) propan-2-ol ((+)-I) Can be.

The compound XI used in the present production method
I is known per se in the literature (see, for example, JP-A-61-72767), but the conventional production method has a low total yield from 4-chlorobenzonitrile (XV) as a starting material, Poor selectivity of trans isomer,
In addition, there are various problems such as including many steps requiring purification by silica gel column chromatography, and it is extremely difficult to carry out this industrially. In the present invention, the above-mentioned problems have been solved, and a process for producing compound XII which can be industrially carried out has been found. That is, compound XII can be produced according to the following reaction formula.

[0024]

Embedded image Step A is carried out by a method known in the literature (JP Idoux et al .), Journal of Organic Chemistry (J. Org. Che).
m. ), 48, 3772, 1983). In this step, 4-chlorobenzonitrile (XV) is reacted with 2,2,3,3-tetrafluoropropanol in the presence of a base such as sodium hydride in an organic solvent such as dimethylformamide or dimethylsulfoxide. It can be done by doing. The compound XVI obtained in this step can be purified by recrystallization from a mixed solvent of an organic solvent such as isopropanol and water. Step B is a step of reducing a cyano group to a formyl group, and is a method known in the literature (JP-A-61-72767). This step is performed by using a reducing agent such as diisobutylaluminum hydride in toluene. Step C is a step of introducing a double bond. In this step, compound (XVII) is reacted with ethyl diethylphosphonoacetate in an organic solvent such as dimethoxyethane or tetrahydrofuran in the presence of a base such as potassium hydroxide or sodium hydride to give (E) -4-
It is intended to obtain ethyl (2,2,3,3-tetrafluoropropoxy) cinnamate (XVIII). This reaction proceeds stereoselectively, and only the desired (E) -isomer is formed, and no formation of the (Z) -isomer is observed. Therefore, purification by silica gel column chromatography is not required. Step D is a conventional ester hydrolysis. The reaction can be carried out in water or an organic solvent such as ethanol or dioxane or a mixed solvent thereof using a base such as sodium hydroxide or potassium hydroxide. Step E is a conventional amidation. In this step, compound XIX is converted to an acid halide with a halogenating reagent such as thionyl chloride, phosphorus pentachloride or the like, and then added to concentrated aqueous ammonia to give compound XX.
Can be obtained. In this step, it is possible to isolate and purify the acid halide, but it is preferable to obtain the compound XX without isolating and purifying the acid halide.
Step F is a step of constructing a triazole ring. In this step, first, in an organic solvent such as methylene chloride, an alkylating agent such as trimethyloxonium tetrafluoroborate is used to form an imino ether compound, and then by reacting formic hydrazide in an organic solvent such as ether. , 3
-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazole (XII) can be obtained. In this step, it is possible to isolate and purify the imino ether compound, but it is preferable to obtain compound XII without isolating and purifying the imino ether compound.

The absolute configuration of the compound (-)-X was found to be (R)
Was determined to be. Reaction Step 5, Step 6, Step 7, Step D, Step 5 ′, Step 6 ′ and Step 7 ′ are all steric retention reactions, and therefore, among the compounds described in the present invention, the following compounds The absolute configuration is as shown below. Compound Absolute configuration (+)-I (R) (-)-I (S) (-)-VII (S) (+)-VII (R) (-)-IX (R) (-)-X (R ) (+)-XI (R) (+)-XIII (S) (-)-XIV (S)

Hereinafter, the active ingredient (+)-2 of the present invention will be described.
-(2,4-difluorophenyl) -1- [3-
[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] -3- (1H-1,2,4-triazole -1-yl) propan-2-ol ((+)-I) and its salts are described as to their effectiveness, usage, dosage and preparation of therapeutic agents.

First, in order to show the efficacy of the compound of the present invention, data on antifungal activity is shown. Test compound Compound (+)-I: (+)-2- (2,4-difluorophenyl) -1- [3-[(E) -4- (2,2,3,
3-tetrafluoropropoxy) styryl] -1H-
1,2,4-triazol-1-yl] -3- (1H-
1,2,4-triazol-1-yl) propane-2-
All compound (-)-I: (-)-2- (2,4-difluorophenyl) -1- [3-[(E) -4- (2,2,3,
3-tetrafluoropropoxy) styryl] -1H-
1,2,4-triazol-1-yl] -3- (1H-
1,2,4-triazol-1-yl) propane-2-
All Compound (±) -I (Compound A): (±) -2- (2,4
-Difluorophenyl) -1- [3-[(E) -4-
(2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl]-
3- (1H-1,2,4-triazol-1-yl) propan-2-ol fluconazole: 2- (2,4-difluorophenyl)
-1,3-bis (1H-1,2,4-triazole-1
-Il) propan-2-ol

EXPERIMENTAL EXAMPLE 1 Determination of Minimum Inhibitory Concentration (MIC) The yeast-like fungus was subload dextrose broth (S
(DB, Difco) at 30 ° C. for 24 hours, and diluted with sterile physiological saline to obtain a bacterial solution of 10 ⁵ cells / ml for inoculation. For filamentous fungi, subload dextrose in the mature stage, where conidia are abundantly formed,
Agar medium (SDA, Difco) slant culture (2 to 3
Weekly culture), 3-5 ml of sterile saline containing 0.05% (w / v) Tween 80 was added, and the inoculating loop (inocul loop) was added.
ating loop, Nunc Inc. ) Was used to release the conidia. After collecting the resulting conidia suspension in sterile pipette, by filtration through sterile gauze 2 ply to remove mycelial clumps and agar pieces were diluted 10 ⁵ conidia / ml with sterile saline And a bacterial solution for inoculation. On the other hand, a drug agar plate is prepared by using dimethyl sulfoxide (DMSO, Wako Pure Chemical) to prepare a drug for 0.00.
The solution was adjusted to a concentration of 5 to 10 mg / ml, and 99 volumes of SDA was added to 1 volume of the drug solution to prepare a two-fold dilution series agar medium having a final concentration of 0.05 to 100 μg / ml. The bacterial solution for inoculation prepared by the above method was inoculated on this agar plate using a micro planter MIT-P (Sakuma Seisakusho). The agar plate was incubated at 30 ° C. for 48 hours, and the minimum concentration at which no fungal growth was visually observed was defined as the minimum inhibitory concentration (MIC). The results are shown in Table 1.

[0029]

[Table 1]

EXPERIMENTAL EXAMPLE 2 Measurement of In vivo Infection Therapeutic Effect Ten male ICR mice per group (body weight 18 to 20 g)
, The test bacteria were intravenously injected as an aqueous suspension and infected. 1 hour after infection or 1 hour after infection
The test compound was orally administered once a day for 5 days.
Two weeks later, the number of surviving animals is counted, and the dose at which 50% of the test animals survive (ED ₅₀ : mg / kg) is determined by Litchfield-Wilcoxon.
(coxon) method. The results are shown in Table 2.

[0031]

[Table 2]

Experimental Example 3 Toxicity test (1) Toxicity test of compound A ((±) -I) in monkeys 1, 3, 10 and 30 mg / kg / day of compound A
Was orally administered to monkeys daily for 28 days, and its toxicity was examined. As a result, at a dose of 3 mg / kg / day or more, a decrease in serum cortisol level, hyperplasia of the adrenocortical bundle and increase in lipid droplets, and atrophy of testicular seminiferous tubules were observed at 30 mg / kg / day.
At the dose of y, prolongation of the electrocardiographic QTc time (QT time corrected by heart rate) was observed. 1m under the conditions of this experiment
A dose of g / kg / day was considered a safe dose. Also,
As a result of examining the time course of the plasma concentration of Compound A using the animal, the plasma concentration increased daily, and reached a steady state 2 or 3 weeks after administration.

(2) Toxicity test of compound (+)-I in monkeys 1, 3, 10 and 30 mg / kg of compound (+)-I
/ Day was orally administered to monkeys daily for 28 days, and its toxicity was examined. As a result, at a dose of 10 mg / kg / day or more, hyperplasia of the adrenocortical bundle and increase in lipid droplets were slightly observed, but serum cortisol levels did not decrease. Other than this mild histological change, no abnormalities were observed on the electrocardiogram, and no toxicity was observed. Under the conditions of this experiment, a dose of 30 mg / kg / day was considered a safe dose. In addition, as a result of examining the change in the plasma concentration of the compound (+)-I using the animal, the plasma concentration did not increase over time.

As is apparent from the above experimental results, the compound (+)-I of the present invention, its salt, solvate and solvate of the salt have a significantly stronger anti-microbial activity than fluconazole either in vitro or in vivo. It was confirmed to exhibit fungal activity. On the other hand, the compound (-) which is the enantiomer
-I showed remarkably weak antifungal activity as compared with the compound (+)-I of the present invention. Furthermore, in the compound (+)-I of the present invention, its pharmacological action and the side effect observed in the compound A are clearly separated. From the above, a drug containing the compound (+)-I of the present invention as an active ingredient has high safety and can be provided as a very useful therapeutic agent for fungal infection.

The compound (+)-I of the present invention is generally used as an excipient, a binder, a lubricant, a coloring agent, a flavoring agent, a suspending agent or an emulsifying agent (for example, polysorbate 80 and gum arabic). Appropriate carriers or solvents, for example, sterile water or vegetable oil, if necessary, and physiologically acceptable solvents or solubilizing agents (eg, alcohol, glycerin, propylene glycol) and the like are appropriately selected and combined to obtain various dosage forms. It can be.

Such dosage forms include tablets, capsules,
Granules, fine granules, powders, suppositories, syrups, inhalants, ointments, emulsions, suspensions, eye drops, aqueous or non-aqueous injections, emulsion or suspension injections Preparations, solid injections that are dissolved in use, emulsion or suspended, and used orally or parenterally (eg, intravenous, intramuscular, subcutaneous, rectal, transdermal or transmucosal absorption, etc.) ) Or by applying it to a pessary or the like. In the case of tablets, capsules, powders, injections, suppositories (systemic) or other systemic administration, the daily dose is 0.1 mg in terms of the amount of the compound of the present invention.
It is preferable to administer 2000 mg, preferably 1 mg-200 mg, but the dose can be appropriately adjusted according to the condition of the patient. It is also possible to administer the whole amount in a single dose or in 2 to 6 divided doses, or to give an intravenous drip.

[0037]

The present invention will be described in more detail with reference to the following examples. Note that the present invention is not limited to the following embodiments. In addition, the optical purity described in the examples is based on a column containing an optically active carrier (DAICEL CHIRA).
It was determined by quantification by HPLC (eluent ethanol: diethylamine = 100: 1) using LCEL OD).

Example 1 4- (2,2,3,3-tetrafluoropropoxy) be
Synthesis of nzonitrile 13.5 g molecular sieves 4
Dimethylformamide 135m
14.4 g of sodium hydride (60% oily substance)
It becomes cloudy and is cooled under ice-cooling with 2,2,3,3-tetrafluoropropane.
43.2 g of phenol was added dropwise. After foaming subsides, 4
-30 g of chlorobenzonitrile was added dropwise under ice cooling,
Stirred at C for 5 hours. 600m of 5% hydrochloric acid aqueous solution
The precipitated crystals were collected by filtration, and water: isopropanol was added.
Recrystallized from 1: 4 (330 ml) to give the title compound 3.
3.7 g were obtained. Melting point: 79.9-80.2 ° C IR spectrum (KBr tablet) ν cm^-1: 222
4,1606,1509,1264,1100  NMR spectrum (90 MHz, CDCl_Three) Δpp
m: 7.65 (2H, d, J = 8.9 Hz), 7.0
0 (2H, d, J = 8.9 Hz), 6.03 (1H, t
t, J = 53.1, 4.3 Hz), 4.41 (2H, t
t, J = 11.9, 1.7 Hz)

EXAMPLE 2 Synthesis of 4- (2,2,3,3-tetrafluoropropoxy) benzaldehyde 4- (2,2,3,3-tetrafluoropropoxy) benzaldehyde obtained in Example 1
167 g of 2,3,3-tetrafluoropropoxy) benzonitrile was dissolved in 680 ml of toluene, and 621 ml of diisobutylaluminum hydride (1.5 M toluene solution) was added dropwise under ice cooling. After stirring at room temperature for 2 hours,
350 ml of toluene was added to the reaction solution, and methanol 280 was added.
ml was added dropwise. The reaction mixture was further diluted with 2M hydrochloric acid (1000).
After stirring for 1 hour, the layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, concentrated under reduced pressure, and 800 ml of methanol and 450 ml of 1M hydrochloric acid were added to the residue.
The mixture was heated and stirred at 40 ° C. for 3 hours. Methanol was distilled off under reduced pressure, 500 ml of 1M hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. After washing with saturated saline, drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure gave 155.4 g of the title compound.
Was obtained as an oil. IR spectrum (thin film) ν cm ^-1 : 1762,1
701, 1604, 1585, 1264, 1106 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 9.90 (1H, s), 7.87 (2H, d, J =
8.6 Hz), 7.06 (2H, d, J = 8.6H)
z), 6.11 (1H, tt, J = 53.1, 4.6H)
z), 4.45 (2H, t, J = 11.9 Hz)

Example 3 Synthesis of ethyl (E) -4- (2,2,3,3-tetrafluoropropoxy) cinnamate 11.6 g of ground potassium hydroxide was suspended in 640 ml of tetrahydrofuran. 23.3 g of ethyl monoacetate was added dropwise, and 4 obtained in Example 2 was further added.
24.5 g of-(2,2,3,3-tetrafluoropropoxy) benzaldehyde was added dropwise. After completion of the dropwise addition, the reaction solution was poured into water, and the precipitated crystals were collected by filtration and air-dried to obtain 25.7 g of the title compound. Melting point: 41.1-42.6 ° C IR spectrum (KBr tablet) ν cm ^-1 : 170
1,1637,1605,1515,1180,112
1,834 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.64 (1H, d, J = 16.2 Hz), 7.5
0 (2H, d, J = 8.9 Hz), 6.93 (2H,
d, J = 8.9 Hz), 6.33 (1H, d, J = 1)
6.2 Hz), 6.05 (1H, tt, J = 53.1,
4.8 Hz), 4.37 (2H, t, J = 11.9H)
z), 4.26 (2H, q, J = 7.1 Hz), 1.3
3 (3H, t, J = 7.1 Hz)

Example 4 Synthesis of (E) -4- (2,2,3,3-tetrafluoropropoxy) cinnamic acid (E) -4-obtained in Example 3
25 g of ethyl (2,2,3,3-tetrafluoropropoxy) cinnamate was dissolved in 250 ml of ethanol, and a solution of 7.5 g of sodium hydroxide dissolved in 50 ml of water was added dropwise at room temperature. One hour later, 50 ml of water was added to dissolve the precipitated crystals, and then ethanol was distilled off under reduced pressure.
The residue was dissolved in 1200 ml of water and adjusted to pH 1 with concentrated hydrochloric acid. The mixture was extracted with 1,000 ml of ethyl acetate, and the ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was washed with hexane, and the obtained crystals were collected by filtration and air-dried to obtain 20.5 g of the title compound. Melting point: 177.4-178.7 ° C IR spectrum (KBr tablet) ν cm ^-1 : 167
6,1627,1603,1512,1220,117
6,1121,1112,832 NMR spectrum (90 MHz, DMSO-d ₆ ) δp
pm: 12.2 (1H, bs), 7.67 (2H, d,
J = 8.6 Hz), 7.55 (1H, d, J = 15.8)
Hz), 7.07 (2H, d, J = 8.6 Hz), 6.
5. 66 (1H, tt, J = 52.0, 5.6 Hz);
40 (1H, d, J = 15.8 Hz), 4.63 (2
H, t, J = 13.5 Hz)

Example 5 Synthesis of (E) -4- (2,2,3,3-tetrafluoropropoxy) cinnamic acid amide (E) -4- (2,2,3) obtained in Example 4 20 g of (3,3-tetrafluoropropoxy) cinnamic acid was heated to reflux with 50 ml of thionyl chloride for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was dissolved in 135 ml of toluene, and this was slowly added dropwise to 50 ml of concentrated aqueous ammonia. 200 ml of ethyl acetate was added to the reaction solution in which crystals were precipitated, and the mixture was extracted.
The extract was washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. After concentrating the ethyl acetate layer under reduced pressure, the residue was washed with 100 ml of a mixed solvent of hexane: ether = 6: 1,
The precipitated crystals were collected by filtration to give 17.5 g of the title compound. Melting point: 147.9-149.8 ° C IR spectrum (KBr tablet) ν cm ^-1 : 318
2,3172,1670,1598,1515,139
9,1259 NMR spectrum (90 MHz, DMSO-d ₆ ) δp
pm: 7.53 (2H, d, J = 8.8 Hz), 7.3
7 (1H, d, J = 15.8 Hz), 7.07 (2H,
d, J = 8.8 Hz), 6.65 (1H, tt, J = 5)
1.9, 5.1 Hz), 6.47 (1H, d, J = 1)
5.8 Hz), 4.60 (2H, t, J = 13.6H)
z)

Example 6 Synthesis of 3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazole Obtained in Example 5 ( E) 52.9 g of 4- (2,2,3,3-tetrafluoropropoxy) cinnamic acid amide was dissolved in 920 ml of anhydrous methylene chloride, and 42.4 g of trimethyloxonium tetrafluoroborate was added.
After refluxing for 5 hours, the reaction solution was washed with a saturated aqueous solution of sodium carbonate ice 1
000 ml, and the methylene chloride layer was separated. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in anhydrous ethanol (265 ml). Formic acid hydrazide (17.2 g) and triethylamine (13.3 ml) were added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated, the residue was dissolved in 600 ml of ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and ether was added to the residue for washing.
36.6 g of the title compound were obtained. Melting point: 153.2 to 154.6 ° C IR spectrum (KBr tablet) ν cm ^-1 : 160
7,1515,1258,1110 NMR spectrum (90 MHz, DMSO-d ₆ ) δp
pm: 8.26 (1H, s), 7.63 (2H, d, J
= 8.8 Hz), 7.48 (1H, d, J = 17.2H)
z), 7.07 (2H, d, J = 8.8 Hz), 7.
03 (1H, d, J = 17.2 Hz), 6.68 (1
H, tt, J = 51.9, 5.7 Hz), 4.62
(2H, t, J = 13.6 Hz)

Example 7 Synthesis of 1,3-dichloro-2- (2,4-difluorophenyl) propan-2-ol 225 g of 2,4-difluorobromobenzene was dissolved in 2000 ml of anhydrous ether. 733 ml of -butyllithium (1.6 M hexane solution) was added dropwise.
One hour later, 148 g of 1,3-dichloroacetone was dissolved in 300 ml of anhydrous ether and added dropwise at -50 ° C. After stirring for 30 minutes, a solution of 76 g of acetic acid in 200 ml of anhydrous ether was added dropwise. Under ice cooling, 500 ml of water was added and the layers were separated. The ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 279 g of the title compound as an oil. IR spectrum (thin film) ν cm ^-1 : 3516, 16
18,1599,1501,1424,1267 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.83 to 7.55 (1H, m), 7.05 to 6.
70 (2H, m), 4.03 (4H, s), 3.02
(1H, bs)

Example 8 1-Chloro-2- (2,4-difluorophenyl)-
Synthesis of 2,3-epoxypropane 45 g of sodium hydride (60% oil) was suspended in 400 ml of dimethylformamide, and the 1,3-dichloro-2- (2,4- A solution of 242 g of difluorophenyl) propan-2-ol in 100 ml of dimethylformamide was added dropwise. The reaction liquid is 750m
The mixture was poured into 1 liter of ice water and adjusted to pH 4 with concentrated hydrochloric acid. Ethyl acetate (1500 ml) was added for extraction, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure. A fraction at 125 to 135 ° C./30 mmHg was collected to obtain 99.5 g of the title compound. Boiling point: 125 to 135 ° C / 30 mmHg IR spectrum (thin film) ν cm ^-1 : 1619,16
02,1508,1425,1272 NMR spectrum (90 MHz, CDCl ₃ ) δ p
pm: 7.57 to 7.31 (1H, m), 6.98 to
6.71 (2H, m), 4.09 (1H, d, J = 1
1.9 Hz), 3.68 (1H, d, J = 11.9H)
z), 3.20 (1H, d, J = 4.8 Hz), 2.9
3 (1H, d, J = 4.8 Hz)

Example 9 Synthesis of 2- (2,4-difluorophenyl) allylic alcohol 1 at 60 ° C
Stirred for hours. To this solution was added a solution of 94 g of 1-chloro-2- (2,4-difluorophenyl) -2,3-epoxypropane obtained in Example 8 in 500 ml of dioxane.
It was added dropwise in 0 minutes. After stirring for 30 minutes, the reaction solution was cooled to room temperature, insolubles were removed by filtration, and air was blown into the filtrate for 30 minutes.
The precipitate was filtered again. The filtrate was extracted with 1000 ml of ether, and the ether layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 77 g of the title compound as an oil. IR spectrum (thin film) ν cm ^-1 : 3340,16
17, 1506, 1420, 1267 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.44 to 7.18 (1H, m), 6.96 to 6.
69 (2H, m), 5.51 (1H, m), 5.35
(1H, bs), 4.46 (2H, m), 1.71-
1.64 (1H, m)

Example 10 (-)-2- (2,4-difluorophenyl) -2,3
Synthesis of Epoxypropanol Titanium tetraisopropoxide (197 ml) was dissolved in methylene chloride (1700 ml), cooled to −20 ° C. under a nitrogen atmosphere, and (+)-diethyl tartrate (164 g) was dissolved in methylene chloride (1).
A 00 ml solution was added. After stirring for 15 minutes, a solution of 113 g of 2- (2,4-difluorophenyl) allyl alcohol obtained in Example 9 in 100 ml of methylene chloride was added dropwise. After stirring for 15 minutes, 332 ml of a 7.1 M solution of t-butyl hydroperoxide in methylene chloride was added dropwise, and
Stirred at C for 8 hours. Add 10% tartaric acid aqueous solution 10
00 ml was added little by little, and the temperature was gradually raised to room temperature. The reaction solution was filtered using celite, a methylene chloride layer was separated from the filtrate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain 90.2 g of the title compound as an oil. Specific rotation: [α] _D = −38 ° (C = 0.97, TH
F) Optical purity (HPLC method): 88% ee IR spectrum (thin film) ν cm ^-1 : 3440,16
18,1508,1271 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.53 to 7.26 (1H, m), 6.99 to 6.
70 (2H, m), 4.09 to 3.89 (2H, m),
3.29 (1H, d, J = 5.1 Hz), 2.84 (1
H, d, J = 5.1 Hz), 1.81 (1H, dd, J)
= 8.3, 5.6 Hz)

Example 11 1-acetoxy-2- (2,4-difluorophenyl)
Synthesis of 2,3-epoxypropane 2.05 g of 1-chloro-2- (2,4-difluorophenyl) -2,3-epoxypropane obtained in Example 8
And 0.98 g of sodium acetate were suspended in 5 ml of acetic acid.
Heated to reflux for an hour. The reaction solution was distilled off under reduced pressure, and the residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate. Ethyl acetate 1
The mixture was extracted with 0 ml, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in 1,2-dimethoxyethane (20 ml), and 400 mg of sodium hydride (60% oil) was added little by little under ice cooling. After stirring for 10 minutes, water 40m under ice cooling
and extracted twice with 40 ml of ethyl acetate. The combined ethyl acetate layers were washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure, and a fraction at 137 to 138 ° C./16 mmHg was collected to obtain 1.37 g of the title compound. Boiling point: 137 to 138 ° C./16 mmHg IR spectrum (thin film) ν cm ⁻¹ : 1751, 15
09,1234,1140,1041,966 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.54 to 7.26 (1H, m), 7.00 to 6.
66 (2H, m), 4.67 (1H, d, J = 12.
5 Hz) 4.15 (1H, d, J = 12.5 Hz),
3.15 (1H, d, J = 5.1 Hz), 2.85
(1H, d, J = 5.1 Hz), 2.02 (3H, s)

Example 12 (+)-2- (2,4-difluorophenyl) -2,3
-Epoxypropanol and (-)-1-acetoxy-
Synthesis of 2- (2,4-difluorophenyl) -2,3-epoxypropane 1-acetoxy-2- (2,4-
Difluorophenyl) -2,3-epoxypropane 20
g was suspended in 440 ml of diisopropyl ether and 4000 ml of 0.1 M phosphate buffer (pH 7.0), and 4.4 g of pig pancreatic lipase (Sigma) was added. 3 at room temperature
After stirring for an hour, the reaction solution was filtered using celite, and the filtrate was extracted twice with 3000 ml of ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
7) and purified by (-)-1-acetoxy-2- (2,4
8.8 g of -difluorophenyl) -2,3-epoxypropane and 7.5 g of (+)-2- (2,4-difluorophenyl) -2,3-epoxypropanol were obtained as oils, respectively. (-)-1-acetoxy-2-
(2,4-difluorophenyl) -2,3-epoxypropane Optical purity (HPLC method): 98% ee IR spectrum (thin film) ν cm ⁻¹ : 1751, 15
09,1234,1140,1041,966 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.54 to 7.26 (1H, m), 7.00 to 6.
66 (2H, m), 4.67 (1H, d, J = 12.5
Hz), 4.15 (1H, d, J = 12.5Hz),
3.15 (1H, d, J = 5.1 Hz), 2.85 (1
H, d, J = 5.1 Hz), 2.02 (3H, s) (+)-2- (2,4-difluorophenyl) -2,3
Epoxypropanol specific rotation: [α] _D = + 37
゜ (C = 1.01, THF) Optical purity (HPLC method): 87% ee IR spectrum (thin film) ν cm ⁻¹ : 3440,16
18,1508,1271 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.53 to 7.26 (1H, m), 6.99 to 6.
70 (2H, m), 4.09 to 3.89 (2H, m),
3.29 (1H, d, J = 5.1 Hz), 2.84 (1
H, d, J = 5.1 Hz), 1.81 (1H, dd, J)
= 8.3, 5.6 Hz)

Example 13 (-)-2- (2,4-difluorophenyl) -2,3
Synthesis of epoxypropanol (-)-1-acetoxy-2- obtained in Example 12
0.40 g of (2,4-difluorophenyl) -2,3-epoxypropane was dissolved in 14 ml of methanol, and 1.75 ml of a 1M aqueous solution of potassium hydroxide was added dropwise at room temperature.
After stirring for 15 minutes, 1 M hydrochloric acid was added to neutralize, and methanol was distilled off under reduced pressure. After extracting twice with 10 ml of ethyl acetate, the extract was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound 0.1.
33 g were obtained as an oil. Specific rotation: [α] _D = −42 ° (C = 1.0, TH
F) Optical purity (HPLC method): 98% ee IR spectrum (thin film) ν cm ^-1 : 3440,16
18,1508,1271 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.53 to 7.26 (1H, m), 6.99 to 6.
70 (2H, m), 4.09 to 3.89 (2H, m),
3.29 (1H, d, J = 5.1 Hz), 2.84 (1
H, d, J = 5.1 Hz), 1.81 (1H, dd, J)
= 8.3, 5.6 Hz)

Example 14 (-)-2- (2,4-difluorophenyl) -3-
Synthesis of (1H-1,2,4-triazol-1-yl) propane-1,2-diol (-)-2- (2,4-difluorophenyl) -2,3- obtained in Example 10. 92 g of epoxy propanol
Is dissolved in 750 ml of tetrahydrofuran,
54 g of 4-triazole and 109 g of anhydrous potassium carbonate were added, and the mixture was heated under reflux for 2 days. Approximately 500 ml of water was added to the reaction solution, the aqueous layer was saturated with sodium chloride, separated, and extracted twice with 800 ml of ethyl acetate. The ethyl acetate layer was concentrated, and 400 ml of chloroform was added to the residue to dissolve the residue.
Then, the resulting mixture was allowed to stand overnight, and the precipitated crystals were collected by filtration. Again, heat and dissolve in 300 ml of chloroform and leave overnight,
The crystals were collected by filtration to obtain 61 g of the title compound. Specific rotation: [α] _D = −60 ° (C = 1.00, TH
F) Optical purity (HPLC method): 100% ee Melting point: 92.1-92.8 ° C IR spectrum (KBr tablet) ν cm ^-1 : 333
0,3130,1654,1560,1517,113
6,1123 NMR spectrum (90 MHz, DMSO-d ₆ ) δp
pm: 8.30 (1H, s), 7.70 (1H, s),
7.53 to 6.82 (3H, m), 5.77 (1H,
s), 5.09 (1H, t, J = 5.6 Hz), 4.5
8 (2H, s), 3.67 (2H, d, J = 5.6H
z) This compound was pulverized well, and about 1 mg was placed in a microvial, to which methylene chloride was added little by little, and the mixture was heated to 40 ° C. 0.5 ml of methylene chloride was added to dissolve. Cover and leave at room temperature. By standing for 4 days or more, about 10 cubic crystals having a size of about 0.1 mm on a side precipitated. The obtained single crystal is converted into a single crystal automatic X-ray structure analyzer AF
Analysis was performed using C-5R (manufactured by Rigaku Corporation), and the absolute configuration was determined to be (R).

Example 15 (+)-2- (2,4-difluorophenyl) -3-
(1H-1,2,4-triazol-1-yl) -2,
Synthesis of 3-epoxypropane (-)-2- (2,4-difluorophenyl) -3- (1H-1,2,4-triazol-1-yl) propane-1,2 obtained in Example 14. -Suspension of 10 g of diol in 1000 ml of anhydrous ether, 27.3 ml of triethylamine and 4.6 ml of methanesulfonyl chloride at room temperature
After stirring for 1 hour, 500 ml of water was added, and the mixture was further stirred for 1 hour. The reaction solution was separated, 500 ml of water was added to the organic layer, and the aqueous layer was adjusted to pH 4 with 1 M hydrochloric acid and separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 7.5 g of the title compound as an oil. Specific rotation: [α] _D = + 4 ゜ (C = 1.04, TH
F) Optical purity (HPLC method): 98% ee IR spectrum (thin film) ν cm ^-1 : 1619,16
01, 1508, 1275, 1140 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 8.06 (1H, s), 7.87 (1H, s),
7.32 to 7.05 (1H, m), 6.93 to 6.72
(2H, m), 4.85 (1H, d, J = 14.8H)
z), 4.49 (1H, d, J = 14.8 Hz), 2.
95 (1H, d, J = 4.3 Hz), 2.88 (1H, d, J = 4.3 Hz)
d, J = 4.3 Hz)

Example 16 (+)-2- (2,4-difluorophenyl) -1-
[3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] -3- (1H-1,2,2,3 Synthesis of 4-triazol-1-yl) propan-2-ol (+)-2- (2,4-difluorophenyl) -3- (1H-1,2,4-triazol- obtained in Example 15 1-yl) -2,3-epoxypropane (42 g) and 3-[(E) -4- (2,2,3,3-
Tetrafluoropropoxy) styryl] -1H-1,
44.2 g of 2,4-triazole and 80.6 g of anhydrous potassium carbonate were suspended in 268 ml of dimethylformamide, and heated and stirred at 90 ° C. for 1 hour. The reaction solution was 1M hydrochloric acid 8
The mixture was poured into 00 ml, extracted with ethyl acetate, washed with water, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting a low-polar substance with ethyl acetate: hexane = 6: 1, and then eluting with ethyl acetate containing 2% methanol). The fractions containing were concentrated, and ether was added to the residue for crystallization. This was heated and dissolved in 700 ml of ethyl acetate, 2400 ml of hexane was added at 50 ° C., and the mixture was allowed to stand at room temperature for 1.5 hours, and the precipitated crystals were collected by filtration. The crystals were dissolved in 100 ml of ethyl acetate, and hexane 3 was added at 50 ° C.
After adding 00 ml, the mixture was allowed to stand at room temperature for 1 hour, and the precipitated crystals were collected by filtration to obtain 18 g of the title compound. Specific rotation: [α] _D = + 50.7 ° (C = 1.01,
THF) Optical purity (HPLC method): 99.5% ee Chemical purity (HPLC method): 99.8% Melting point: 92.0-93.4 ° C. IR spectrum (KBr tablet) ν cm ⁻¹ : 313
0,1618,1606,1515,1500,111
4 NMR spectrum (90 MHz, DMSO-d ₆ ) δp
pm: 8.32 (1H, s), 8.28 (1H, s),
7.77 (1H, s), 7.59 (2H, d, J = 8.
6 Hz), 7.34 (1H, d, J = 16.2 Hz),
7.04 (2H, d, J = 8.6 Hz), 6.90 (1
H, d, J = 16.2 Hz), 7.35 to 6.86 (3
H, m), 6.66 (1H, tt, J = 51.8,
5.6 Hz), 6.37 (1 H, s), 4.88-4.
45 (6H, m)

Example 17 (+)-2- (2,4-difluorophenyl) -3-
Synthesis of [3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] propane-1,2-diol (+)-2- (2,4-difluorophenyl) -2,3-epoxypropanol obtained in Example 12 0.45
g and 3-[(E) -4- (2,2,2) obtained in Example 6.
3,3-tetrafluoropropoxy) styryl] -1H
0.60 g of -1,2,4-triazole was dissolved in 20 ml of dimethylformamide, 0.28 g of potassium carbonate was added, and the mixture was stirred at 80 to 90 ° C. for 3 hours. After cooling, 50 ml of water was added to the reaction solution, and the mixture was extracted three times with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane- 1: 5-1: 1 ) to obtain 0.42 g of the title compound. Specific rotation: [α] _D = + 57.4 ° (C = 1.02,
THF) Optical purity (HPLC method): 88% ee Melting point: 119.8-120.8 ° C IR spectrum (KBr tablet) ν cm ^-1 : 344
6,1607,1516,1499,1261,112
6 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.86 (1H, s), 7.68 to 7.40 (4
H, m), 6.96 to 6.66 (5H, m), 6.06.
(1H, tt, J = 53.1, 5.0 Hz), 4.71
(2H, s), 4.36 (2H, t, J = 11.7H)
z), 4.03 (1H, d, J = 11.7 Hz);
75 (1H, d, J = 11.5Hz)

Example 18 (-)-2- (2,4-difluorophenyl) -1-
Synthesis of [3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] -2,3-epoxypropane (+)-2- (2,4-difluorophenyl) -3- [3-[(E) -4- (2,2) obtained in Example 17
3,3-tetrafluoropropoxy) styryl] -1H
-1,2,4-triazol-1-yl] propane-
300 mg of 1,2-diol was dissolved in 30 ml of anhydrous ether, and 0.07 ml of methanesulfonyl chloride and 0.43 ml of triethylamine were added. After stirring for 30 minutes, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 25 ml of dimethylformamide, and 50 mg of sodium hydride (60% oil) was added. After stirring at room temperature for 4 hours, 50 ml of water was added to the reaction solution, and the mixture was extracted three times with 40 ml of ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to obtain 187 mg of the title compound. Specific rotation: [α] _D = 11.8 ° (C = 0.76
5, THF) Optical purity (HPLC method): 87% ee Melting point: 129.8-132.3 ° C IR spectrum (KBr tablet) ν cm ^-1 : 161
9, 1509, 1271, 1214, 1138, 110
1 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.99 (1H, s), 7.60 to 6.73 (9
H, m), 6.07 (1H, tt, J = 53.1,4.
9 Hz), 4.80 (1H, d, J = 15.2 Hz),
4.48 (1H, d, J = 15.2 Hz), 4.36
(2H, t, J = 11.7 Hz), 2.98 (1H,
d, J = 4.8 Hz), 2.88 (1H, d, J = 4.
8Hz)

Example 19 (+)-2- (2,4-difluorophenyl) -1-
[3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] -3- (1H-1,2,2 Synthesis of 4-triazol-1-yl) propan-2-ol 22 mg of 1,2,4-triazole was dissolved in 3 ml of dimethylformamide, and 14 mg of sodium hydride (60% oil) was added. Example 1 after foaming subsided
(-)-2- (2,4-difluorophenyl) -1- [3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H- 1,2,
4-Triazol-1-yl] -2,3-epoxypropane (150 mg) in dimethylformamide (3.5 ml) was added dropwise. After stirring at room temperature for 16 hours, 4 mg of sodium hydride (60% oil) and 1,2,4-
An additional 7 mg of triazole was added. After further stirring at room temperature for 4 hours, 80 ml of water was added, and the mixture was extracted twice with 80 ml of ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate). The fraction containing the desired product was concentrated, the residue was dissolved by heating in 2 ml of ethyl acetate, 9 ml of hexane was added at 50 ° C., the mixture was allowed to stand at room temperature, and the precipitated crystals were collected by filtration to obtain 60 mg of the title compound. Optical purity (HPLC method): 96% ee Melting point: 92.0 to 93.4 ° C IR spectrum (KBr tablet) ν cm ^-1 : 313
0,1618,1606,1515,1500,111
4 NMR spectrum (90 MHz, DMSO-d ₆ ) δp
pm: 8.32 (1H, s), 8.28 (1H, s),
7.77 (1H, s), 7.59 (2H, d, J = 8.
6 Hz), 7.34 (1H, d, J = 16.2 Hz),
7.04 (2H, d, J = 8.6 Hz), 6.90 (1
H, d, J = 16.2 Hz), 6.86 to 7.42 (3
H, m), 6.66 (1H, tt, J = 51.8, 5.
6Hz), 6.37 (1H, s), 4.88-4.45
(6H, m)

Example 20 (+)-2- (2,4-difluorophenyl) -1-
[3-[(E) -4- (2,2,3,3-tetrafluoro)
Lopropoxy) styryl] -1H-1,2,4-tria
Zol-1-yl] -3- (1H-1,2,4-tria
Zol-1-yl) propan-2-ol monosulfate
Synthesis of (+)-2- (2,4-difluoro obtained in Example 16
Rophenyl) -1- [3-[(E) -4- (2,2,
3,3-tetrafluoropropoxy) styryl] -1H
-1,2,4-triazol-1-yl] -3- (1H
-1,2,4-triazol-1-yl) propane-2
-Dissolve 100 mg of all in 1 ml of ethanol,
A solution of 18.2 mg of acid dissolved in 0.5 ml of ethanol
Was added and allowed to stand for 2 hours. The precipitated crystals are collected by filtration and air-dried.
After that, it was dissolved by heating in 3 ml of ethanol. 16:00 at room temperature
After standing for a while, the precipitated crystals were collected by filtration and air-dried. Obtained
The crystals were suspended in 2 ml of acetone and sonicated for 2 hours.
After filtration, the crystals were dried under reduced pressure to give 55 mg of the title compound. Elemental analysis: C₂₄H₂₀N₆O₂F₆・ H₂SO₄  Obtained value C (44.82%), H (3.43%), N (12.75%) Calculated value C (45. 29%), H (3.48%), N (13.20%) Melting point: 189-193 ° C IR spectrum (KBr tablet) ν cm^-1: 160
6,1514,1262,1202,1178,112
4,620 NMR spectrum (90 MHz, DMSO-d₆) Δ
ppm: 8.52 (1H, s), 8.37 (1H,
s), 7.93 (1H, s), 7.75 to 6.81 (9
H, m), 6.03 (1H, tt, J = 51.8, 5.
6Hz), 4.85 to 4.46 (6H, m)

Example 21 Optical isomerization of 2- (2,4-difluorophenyl) -2,3-epoxypropanol

First step (+)-1-chloro-2-
Synthesis of (2,4-difluorophenyl) -2,3-epoxypropane (+)-2- (2,4-difluorophenyl) -2,3-epoxypropanol obtained in Example 12 1.07
g of triphenylphosphine and 1.7 g of carbon tetrachloride.
Then, the mixture was dissolved in ml and heated under reflux for 7 hours. 20ml of water after cooling
And extracted twice with 20 ml of methylene chloride. The organic layers were combined, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 97) to obtain 0.71 g of the title compound as an oil. IR spectrum (thin film) ν cm ^-1 : 1619, 16
02,1508,1425,1272 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.57 to 7.31 (1H, m), 6.98 to 6.
71 (2H, m), 4.09 (1H, d, J = 11.9)
Hz), 3.68 (1H, d, J = 11.9 Hz),
3.20 (1H, d, J = 4.8 Hz), 2.93 (1
H, d, J = 4.8 Hz)

Second step (-)-1-acetoxy-2-
Synthesis of (2,4-difluorophenyl) -2,3-epoxypropane (+)-1-chloro-2- (2,4) obtained in the first step
The same operation as in Example 11 was carried out using 0.70 g of-(difluorophenyl) -2,3-epoxypropane to obtain 0.55 g of the title compound as an oil. IR spectrum (thin film) ν cm ⁻¹ : 1751, 15
09,1234,1140,1041,966 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.54 to 7.26 (1H, m), 7.00 to 6.
66 (2H, m), 4.67 (1H, d, J = 12.5
Hz), 4.15 (1H, d, J = 12.5 Hz),
3.15 (1H, d, J = 5.1 Hz), 2.85 (1
H, d, J = 5.1 Hz), 2.02 (3H, s)

Third Step Synthesis of (-)-2- (2,4-difluorophenyl) -2,3-epoxypropanol (-)-1-acetoxy-2- obtained in the second step
The same operation as in Example 13 was performed using 0.40 g of (2,4-difluorophenyl) -2,3-epoxypropane to obtain 0.33 g of the title compound as an oil. Optical purity (HPLC method): 98% ee IR spectrum (thin film) ν cm ^-1 : 3440,16
18,1508,1271 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.53 to 7.26 (1H, m), 6.99 to 6.
70 (2H, m), 4.09 to 3.89 (2H, m),
3.29 (1H, d, J = 5.1 Hz), 2.84
(1H, d, J = 5.1 Hz), 1.81 (1H, d
d, J = 8.3, 5.6 Hz)

Example 22 Synthesis of 1- (2,4-difluorophenyl) cyclopropanol 1,3-dichloro-2- (2,4-
Difluorophenyl) propan-2-ol (2.5 g) was dissolved in anhydrous ether (20 ml), and while stirring vigorously under ice-cooling, ethylmagnesium bromide ether (40 m2) prepared from 7.91 g of ethyl bromide and 1.84 g of magnesium.
l) A solution and a solution of ferric chloride in ether (10 ml) were simultaneously added dropwise over 2 hours. After stirring at room temperature for 1 hour, the reaction solution was poured into a mixture of 80 g of ice and 30 ml of 2M hydrochloric acid saturated with ammonium chloride, and the ether layer was separated. After the aqueous layer was extracted with 50 ml of ether, the ether layers were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
1: 9) to give 0.99 g of the title compound as an oil. IR spectrum (thin film) ν cm ^-1 : 1617, 16
04, 1508, 1234, 1140, 1115, 96
9,851 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.51 to 6.69 (3H, m), 2.53 (1
H, d, J = 1.7 Hz), 1.18 to 0.89 (4
H, m)

Example 23 Synthesis of 1- (2,4-difluorophenyl) -1-methanesulfonyloxycyclopropane 0.97 g of 1- (2,4-difluorophenyl) cyclopropanol obtained in Example 22 and triethylamine To a solution obtained by dissolving 0.63 g in 8 ml of anhydrous ether was added 0.72 g of methanesulfonyl chloride under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was 1 M hydrochloric acid (15 ml)
The mixture was poured into the flask, stirred well, and then separated. The ether layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1.26 g of the title compound as an oil. IR spectrum (thin film) ν cm ^-1 : 3089, 29
41,1509,1363,1171 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.62 to 6.74 (3H, m), 2.68 (3
H, s), 1.76 to 1.08 (4H, m)

Example 24 Synthesis of 2- (2,4-difluorophenyl) allyl alcohol 1- (2,4-difluorophenyl) -1-methanesulfonyloxycyclopropane obtained in Example 23
0 g and 0.444 g of calcium carbonate were added to a mixed solvent of 10 ml of water and 10 ml of acetone, followed by stirring at 50 ° C. for 10 hours. The reaction solution was extracted with 400 ml of ether, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to obtain 0.39 g of the title compound as an oil. IR spectrum (thin film) ν cm ^-1 : 3340,16
17, 1506, 1420, 1267 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.44 to 7.18 (1H, m), 6.96 to 6.
69 (2H, m), 5.51 (1H, m), 5.35
(1H, bs), 4.46 (2H, m), 1.71-
1.64 (1H, m)

Example 25 Synthesis of 2- (2,4-difluorophenyl) -1,2-epoxypropane 8.5 g of sodium hydride (60% oily substance) was suspended in 170 ml of dimethyl sulfoxide, and cooled under ice cooling. 42.8 g of trimethylsulfoxonium bromide are added little by little, and then, at 50 ° C., 2,4-difluoroacetophenone 2
A solution obtained by dissolving 7.6 g in 140 ml of dimethyl sulfoxide was added dropwise. After stirring at 50 ° C. for 4 hours, the reaction solution was poured into 1 liter of ice water and extracted with 800 ml of ether. The aqueous layer was further extracted twice with 500 ml of ether, and the combined ether layers were washed three times with water, then once with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure, and 90-92 ° C./40 mmH
g fractions were collected to give 17.2 g of the title compound. Boiling point: 90-92 ° C / 40 mmHg IR spectrum (thin film) ν cm ^-1 : 2985,16
17, 1604, 1507, 1424, 1271, 11
40,967,851 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.42 to 6.70 (3H, m), 2.95 (1
H, d, J = 5.3 Hz), 2.78 (1H, d, J =
5.3Hz), 1.65 (3H, s)

Example 26 Synthesis of 2- (2,4-difluorophenyl) allyl alcohol 2.18 g of 2- (2,4-difluorophenyl) -1,2-epoxypropane obtained in Example 25 was mixed with 25 ml of acetonitrile. And 6 ml of 1,8-diazabicyclo [5.4.0] -7-undecene was added. After 4 ml of iodotrimethylsilane was added dropwise thereto, the mixture was heated under reflux for 20 hours. The reaction solution was poured into water, and 3
The mixture was extracted twice, and the organic layer was washed with 1M hydrochloric acid and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain 0.4 g of the title compound as an oil. IR spectrum (thin film) ν cm ^-1 : 3340,16
17, 1506, 1420, 1267 NMR spectrum (90 MHz, CDCl ₃ ) δpp
m: 7.44 to 7.18 (1H, m), 6.96 to 6.
69 (2H, m), 5.51 (1H, m), 5.35
(1H, bs), 4.46 (2H, m), 1.71-
1.64 (1H, m)

Next, (+)-2- (2,2) was used as the active ingredient.
4-difluorophenyl) -1- [3-[(E) -4-
(2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl]-
Examples of preparations containing 3- (1H-1,2,4-triazol-1-yl) propan-2-ol (compound I) or a salt thereof will be described, but the present invention is limited to the following examples. Not something.

Example A Tablet Compound (+)-I 100 g Polyethylene glycol 6000 100 g Sodium lauryl sulfate 15 g Corn starch 30 g Lactose 250 g Magnesium stearate 5 g After weighing the above components, polyethylene glycol 600
0 was heated to 70-80 ° C., and the compound of the present invention, sodium lauryl sulfate, corn starch and lactose were added thereto, and the mixture was cooled as it was. The solidified mixture is granulated in a pulverizer. The granules are mixed with magnesium stearate and compressed and compressed into tablets weighing 250 mg.

Example B Capsule Compound (+)-I • monosulfate 100 g Lactose 250 g Corn starch 50 g Microcrystalline cellulose 95 g Magnesium stearate 5 g After weighing the above components, four components other than magnesium stearate were mixed uniformly. I do. After adding the magnesium stearate, mix for a few more minutes. The mixed fraction was placed in a No. 25 in one hard capsule
Fill in 0 mg each to make a capsule.

Example C Suppository Compound (+)-I 50 g Polyethylene glycol 1500 200 g Polyethylene glycol 4000 750 g The compound I of the present invention was sufficiently polished in a mortar to obtain a fine powder, and then 1 g of each suppository was prepared by a melting method. Make an agent.

[0071]

INDUSTRIAL APPLICABILITY The compound of the present invention has a strong antifungal activity, and its pharmacological action and the toxicity of compound A are clearly separated, so that it has high safety. Therefore, a drug containing the compound of the present invention as an active ingredient is extremely useful as a therapeutic or prophylactic agent for fungal infection. The present invention also provides a production method useful for stereoselectively and industrially producing such an excellent optically active antifungal agent.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication location C07C 309/66 7419-4H C07C 309/66 309/73 7419-4H 309/73 C07D 301/19 C07D 301/19 303/14 303/14 303/16 303/16 405/06 249 // C07B 53/00 7419-4H C07B 53/00 B C07C 67/343 C07C 67/343 69/736 69 / 736 (C07D 405/06 249: 00 303: 00)

Claims (15)

(57) [Claims] 1. The following formula ((+)-I) (In the formula, * indicates optical activity) (+)-2- (2,4-difluorophenyl) -1-
[3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] -3- (1H-1,2,2 4-triazol-1-yl) propan-2-ol, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the salt thereof. 2. The following formula (II): (In the formula, * represents optical activity, and A and A ′
Represents together an oxygen atom, or A ′ represents a hydroxyl group and A represents a hydroxyl group, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and R represents a hydroxyl group, an acetoxy group, 1H-1,2,4-triazole Represents a -1-yl group or a 3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl group, provided that A And R are not hydroxyl groups at the same time) (-)-or (+)-2-
(2,4-difluorophenyl) -propane derivative. 3. The compound according to claim 2, wherein A and A ′ together represent an oxygen atom. 4. The compound according to claim 2, wherein A and A ′ both represent a hydroxyl group. 5. The compound according to claim 3, wherein R is a hydroxyl group or an acetoxy group. 6. R is 1H-1,2,4-triazole-
The compound according to claim 3, which is a 1-yl group. 7. When R is 3-[(E) -4- (2,2,3,
3-tetrafluoropropoxy) styryl] -1H-
4. A 1,2,4-triazol-1-yl group.
A compound as described. 8. R is 1H-1,2,4-triazole-
The compound according to claim 4, which is a 1-yl group. 9. The method of claim 3, wherein 3-[(E) -4- (2,2,3,3-
Tetrafluoropropoxy) styryl] -1H-1,
The compound according to claim 4, which is a 2,4-triazol-1-yl group. 10. The following formula ((−)-VII): (In the formula, * indicates optical activity) (-)-2- (2,4-difluorophenyl) -2,3
1,2,4-epoxypropanol in the presence of a base
A triazole is allowed to act, then the primary hydroxyl group is activated with methanesulfonyl chloride, and then converted into an epoxide under basic conditions. Then, in the presence of a base, the following formula (XII) 3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4 represented by
-The following formula ((+)-I) characterized by allowing triazole to act: (In the formula, * indicates optical activity) (+)-2- (2,4-difluorophenyl) -1-
[3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] -3- (1H-1,2,2,3 4-Triazol-1-yl) propan-2-ol, a pharmaceutically acceptable salt thereof, a solvate thereof, or a method for producing a solvate of the salt thereof. 11. The following formula ((+)-VII): (In the formula, * indicates optical activity) (+)-2- (2,4-difluorophenyl) -2,3
The following formula (XI) in the presence of a base in epoxypropanol
I) 3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4 represented by
-Acting a triazole, then activating the primary hydroxyl group with methanesulfonyl chloride, converting it into an epoxide under basic conditions, and then reacting 1,2,4-triazole in the presence of a base. ((+)-I) (In the formula, * indicates optical activity) (+)-2- (2,4-difluorophenyl) -1-
[3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] -3- (1H-1,2,2,3 4-Triazol-1-yl) propan-2-ol, a pharmaceutically acceptable salt thereof, a solvate thereof, or a method for producing a solvate of the salt thereof. 12. The following formula (VI): Asymmetric oxidation of 2- [2,4-difluorophenyl) allyl alcohol represented by the following formula with t-butyl hydroperoxide in the presence of titanium tetraisopropoxide and diethyl (+)-tartrate. Characteristic formula ((-)-VII) (In the formula, * indicates optical activity) (-)-2- (2,4-difluorophenyl) -2,4
-A process for producing epoxypropanol. 13. The following formula (VI): Asymmetric oxidation of 2- (2,4-difluorophenyl) allyl alcohol represented by Characteristic formula ((+)-VII) (In the formula, * indicates optical activity) (+)-2- (2,4-difluorophenyl) -2,3
-A process for producing epoxypropanol. 14. The following formula ((±) -IX) 1-acetoxy-2- (2,4-difluorophenyl) -2,3-epoxypropane represented by the following formula ((+)-VI
I) (In the formula, * indicates optical activity) (+)-2- (2,4-difluorophenyl) -2,3
-The following formula ((-)-IX), which is obtained and recovered by epoxypropanol: (In the formula, * indicates optical activity) (−)-1-acetoxy-2- (2,4-difluorophenyl) -2,3-epoxypropane, By decomposition, the following formula ((-)-VII) is obtained. (In the formula, * indicates optical activity) (-)-2- (2,4-difluorophenyl) -2,3
-Obtaining epoxypropanol,
Optically active 2- (2,4-difluorophenyl) -2,
A method for producing 3-epoxypropanol. 15. The following formula ((+)-I) (In the formula, * indicates optical activity) (+)-2- (2,4-difluorophenyl) -1-
[3-[(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl] -3- (1H-1,2,2,3 4-triazol-1-yl) propan-2-ol, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the salt thereof as an active ingredient.