JPH04208269A - New triazole derivative and salt thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> is aryl or heterocyclic ring bonded through C; R<2> is H, F, alkyl, etc.; R<3> is H, alkyl, cycloalkyl; R<2> and R<2> with C form cycloalkyl ring; R<4> and R<5> are alkyl, alkenyl, aryl or heterocyclic bonded through C) and a salt thereof. EXAMPLE:2-(2,4-Difluorophenyl)-4-methyl-1-(1H-1,2,4-triazol-1-yl)-2,4- pentanediol. USE:An antifungal agent having excellently antifungal activity and high safety. PREPARATION:A compound shown by formula II (X is halogen) or a compound shown by formula III is reacted with a compound shown by formula IV or a salt thereof in a solvent (e.g. N,N-dimethylformamide) or in a solventless state at 20-100 deg.C for 1024 hours to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to novel triazole derivatives and salts thereof that have antifungal activity and exhibit excellent therapeutic effects on human and animal diseases.

Therefore, the object of the present invention is to exhibit excellent antifungal activity,
Our objective is to provide compounds that exhibit excellent therapeutic effects on human and animal diseases.

[Prior art] Amphotericin B is currently used as a treatment for deep mycoses.
(U.S. Pat. No. 2,908,611) and flucytosine (
U.S. Patent No. 2802005) is mainly used,
Furthermore, as azole antifungal agents, for example,
Conazole (Japanese Unexamined Patent Publication No. 53-95973) and fluconazole (Japanese Unexamined Patent Publication No. 58-32868) have been reported to be useful as therapeutic agents for fungal diseases.

``Problem to be solved by the invention'' However, the above therapeutic agents cannot be said to be satisfactory in terms of pharmacokinetics, toxicity, antibacterial spectra, etc., and the development of even better compounds is desired. Ta.

[Means for Solving the Problem] Under these circumstances, the present inventors conducted intensive research and found that the following general formula [I] [wherein R1 is an optionally substituted aryl] or a heterocyclic group bonded via a carbon atom in the ring, R2 is a hydrogen atom, a fluorine atom, an alkyl or cycloalkyl group, and R3 is a hydrogen atom, an alkyl or cycloalkyl group; or R2
, and a cycloalkyl ring formed by forming H with the carbon atom to which R3 is bonded; R and R5 are the same or different, and are optionally substituted alkyl, cycloalkyl, alkenyl, aryl, or a carbon atom in the ring Indicates a heterocyclic group bonded via. A novel triazole derivative represented by `` and its salt has excellent antifungal activity,
We have discovered that it has excellent absorbability and exhibits excellent internal dynamics, and have completed the present invention.

The compounds of the present invention will be described in detail below.

Unless otherwise specified in this specification, a halogen atom refers to, for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; an alkyl group refers to, for example, a methyl,
C alkyl groups such as ethyl, n-propyl, isopropyl, lobutyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl; n-
propoxy, impropoxy, n-butoxy, iso11
~C alkoxy groups such as xy, dibutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy; alkoxycarbonyl groups include, for example, methoxycarbonylpoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl , iso71-xycarbonyl and ter
t-butoxycarbonyl etc.' C a1-4 lukoxy GO- group; alkylthio group is, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, seanobutylthio, tert-butylthio, C such as pentylthio, hexylthio, heptylthio and octylthio
Alkylthio groups; 1-10 Aryl groups include, for example, phenyl and naphthyl groups; Cycloalkyl groups include, for example, C cyclo3-8 alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cycloheptyl; Alkenyl groups include, for example, vinyl,
C2-1 such as propenyl and butenyl.

Alkenyl group; Examples of the halo-lower alkyl group include fluoromethyl, chloromethyl, trifluoromethyl, trichloromethyl, 2,2.2-trifluoroethyl, 1,1,2,2.2-pentafluoroethyl and 1, 1, 2, 2, 3.

A C alkyl group substituted with a halogen atom such as 3,3-heptafluoropropyl; heterocyclic groups include, for example, thienyl, furyl, imidazolyl, triazolyl, pyrazolyl, thiazolyl, isodeazolyl, oxasilyl, isodeazolyl, thiadiazolyl, pyridyl. ,
A 5- or 6-membered heterocyclic group containing at least one oxygen, sulfur or nitrogen atom such as pyridazyl, pyrimidyl, pyrazyl and triazyl; and "lower" represents a C group, respectively.

The heterocyclic group bonded via a carbon atom in the ring of 1-4 R , R and R5 includes a 5- or 6-membered heterocyclic group containing one or more oxygen, sulfur or nitrogen atoms, for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyran-3-yl, pyrrol-3-yl, imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, iso Thiazol-3-yl, isoxazol-3-yl, pyridin-2-yl, pyridin-
3-yl, 1-oxide-pyridin-3-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrrolidin-2
-yl, 2-pyrrolin-3-yl, imidazolidine-2
-yl, 2-imidacillin-4-yl, piperidine-2
-yl and morpholin-3-yl.

Examples of the cycloalkyl ring formed by combining the carbon atoms to which R2 and R3 are bonded include cyclopropane, cyclobutane, cyclopentane, and cyclobutane.

The name tree in R1, R4 and R5 is, for example, one or more selected from a halogen atom, lower alkyl, lower alkoxy, lower alkylthio, hydroxyl, cyano, amine, carbamoyl, alkoxycarbonyl, lower alkyl, and heterocyclic group. may be substituted with a substituent.

- Salts of the compound of formula [I] include pharmaceutically acceptable salts, for example salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; acetic acid, fumaric acid, maleic acid, malic acid, alcohol 15 salts with carboxylic acids such as citric acid, oxalic acid and aspartic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

The compounds of the present invention include essentially all isomers, geometric isomers,
(optical isomers), hydrates and all crystalline forms.

The novel triazole derivative of general formula [I] or a salt thereof is generally produced by combining methods known per se, and for example, it can be produced by the method shown below.

(The following is a blank space) Manufacturing method 1 R3, R4 and R5 have the same meanings as described above. ” By reacting the compound of general formula [1] or [13 with the compound of formula [lv] or a salt thereof, the compound of formula [I] or a salt thereof can be obtained.

Examples of salts of the compound of general formula "1■" include salts with alkali metals such as potassium onibis l-lium; and triethylamine, tributylamine and 1,8
-diazabicyclo[5,4,01undec-7-ene (
Examples include salts with organic bases such as DBU). Moreover, these salts can also be produced within the reaction system.

This reaction can be carried out in the presence or absence of a solvent, and the solvent used is not particularly limited as long as it does not adversely affect the reaction, but for example, N,
Amides such as N-dimethylformamide and N,N-dimethylacetamide; alcohols such as methanol and ethanol; ethers such as diethyl ether and tetrahydrofuran; aromatic hydrocarbons such as benzene and toluene; nitriles such as acetonitrile; Examples include dimethyl sulfoxide; sulfolane; and water, and two or more of these solvents may be used in combination.

The amount of the compound of general formula r-IV or its salt to be used is:
- for the compound of Formula III] or [11], 1 to
It is sufficient to use 10 times the molar amount.

This reaction may normally be carried out at 20 to 100°C for 1 to 24 hours.

Production method 2 In formula 1, R represents a carboxyl protecting group; Yl and Y-
represents the nor\logen atoms: R1, R2, R, R and R5
does not have the same meaning as above. ” Examples of the salt of the compound of the general formula [Ial or [VII] include the same salts as the salts of the compound of the general formula [I].

Examples of the carboxyl-protecting group for R6 include common carboxyl-protecting groups, such as lower alkyl groups.

(1) - By reacting the compound of the formula [V] with the compound of the formula [VIal or [VIbl], the compound of the formula [Ial or its salt or the compound of the general formula [VI] or its salt is reacted, respectively. Obtainable.

This reaction can be carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not adversely affect the reaction, but examples include diethyl ether, tetrahydrofuran, and 1°2-dimethoxyethane. Examples include ethers, and two or more of these solvents may be used in combination.

The compound of general formula [VIal or [VIbl] may be used in a molar amount 1 to 10 times that of the compound of formula [V].

This reaction may normally be carried out at -80 to 100°C for 1 to 24 hours under an inert gas.

The compound of the formula [VI[] or its salt can be separated from the compound of the formula [I al or its salt] by conventional isolation and purification operations such as column chromatography and recrystallization.

(ii) - the compound of formula [W] or a salt thereof, -
By reacting a compound of formula [VIC] or [VId], a compound of formula [i] or a salt thereof can be obtained.

This reaction can be carried out according to the method described in (i) above.

Next, the compounds of general formulas [II], [I[I] and [V] which are raw materials for producing the compounds of the present invention! ! The construction method will be explained.

The compound of general formula [V] is disclosed in JP-A No. 59-82376,
JP-A-62-249978 and JP-A-1-2497
55Q, etc., or a method similar thereto.

Compounds of general formulas [IIi and [I] can be produced, for example, according to the production method not shown below.

C C C C "In the formula, Y3 represents a halogen atom: R1, R2, R3,
R4, R5, R6, X, Yl and Y2 have the same meanings as described above. ”-The compound of the formula [■] can be produced by a known method or a method analogous thereto.

Next, each process will be explained.

(1) - Preparation of compounds of formulas [Xl and [XI].

- To the compound of the formula [■], in the presence of a solvent, - the compound of the formula [IX]
al, [IXbl or [IXC], respectively - by reacting compounds of the formula [Xl or [
XI] can be obtained.

This method can be carried out according to the method described in Tetrahedron Lett, Vol. 25, p. 2301 (1984), JP-A-59-82376 or JP-A-62-249978. can.

(ii) - Production of compounds of formulas [n] and [111].

- to the compound of the formula [Xl or [XI], - to the compound of the formula [VI
By reacting a compound of aJ or [VIbl, respectively, a compound of formula [Xl[] or [X1ll] is obtained, and a compound of formula [VIC] or [VIdl] is obtained.
By reacting a compound of -formula [n] or [I[I], respectively, a compound of formula [n] or [I[I] can be obtained.

This reaction can be carried out according to Production Method 2.

In addition, the compound of formula [VI] or its salt can be prepared by manufacturing method 2.
In addition to the method described above, it can be manufactured, for example, by the method shown below.

"In the formula, R1, R2, R3, R4 and Yl have the same meanings as described above." (1) - Formula [XIV] (7) The compound is
It can be produced by the method described in No. 9864 or a method similar thereto.

(ii) -The compound of the formula [XV] is the compound of the formula [X[
'/] to the compound with the formula [VIal or [VIbl
It can be obtained by reacting the following compounds.

This method can be performed according to Production Method 2.

0ii) - The compound of formula [VI] or a salt thereof is,
- It can be obtained by reacting the compound of formula [XV] with an oxidizing agent.

This method is described in the Journal φ on Chemical φ Society (J, 8m, Chem, Soc, ) Volume 87,
It can be carried out according to the method described on page 4214 (1965).

Moreover, - in the compound of formula [VI] or a salt thereof,
A compound in which R and R are hydrogen atoms and R4 is a methyl group can be obtained by reacting the compound of formula [■] with the compound of formula [1v] and acetone in the presence of a base such as sodium carbonate or potassium carbonate. can be obtained by

This reaction uses acetone as a solvent and under reflux,
It may be carried out for 0.5 to 10 hours.

The compound of general formula [I] or a salt thereof thus obtained can be isolated and purified by conventional methods such as extraction, crystallization, distillation, and column chromatography.

In addition, the compound of the formula [E] or its salt can be converted into other general formulas by appropriately combining methods known per se, such as oxidation reaction, reduction reaction, addition reaction, substitution reaction, deprotection, and hydrolysis reaction. It can be derived from the compound [I] or a salt thereof.

Pharmaceutically, when the compound of the present invention is used as a medicine.

Additives such as acceptable excipients, carriers and diluents may be mixed as appropriate, and these can be prepared into tablets, capsules, etc. by conventional methods. It can be administered orally or parenterally in the form of granules, fine granules, powders, or injections. In the case of oral administration, the dose is usually about 0.05 to 200 my/day per 11 kg of adult body weight, and this is administered in one or several doses (administered in batches, depending on age, body weight, and symptoms). be selected accordingly.

[Effects of the Invention] Next, the pharmacological actions of representative compounds of the present invention will be described.

Hey, test compound N used in the following pharmacological tests.

cited the Tora example number and also used fluconazole and ketoconazole as control compounds in each test.

1. Minimum Inhibitory Concentration (MIC) Mariotsudo ()1. S. Harriott) method [2
5th■nterscience C011feren
Ce On AlltimiCrObialAgent
s and (1) emotherapy page 243 (
(1985)].

Candida albicans
cans) ON-28 is Zaburo Dextrose.
Agar (Sabouraud de Xtrose ag)
ar) Medium (neopep) 10g, glucose 20g,
The cells were cultured in 15 g/l agar at 30°C for 11 to 2 days and suspended in sterile distilled water.

Aspergillus fumigatus
Sfumigatus) JAN-3006 is potato dextrose agar (Potato dextrose)
The conidia were cultured at 30°C in rose agar medium (Hakusui Seiyaku) until abundant conidia were formed, and the formed conidia were suspended in sterile physiological saline containing 0.6% Rween 80. . Candida albicans or Aspergillus fumigatus was grown in FC broth medium containing drugs (yeast carbon base 1.179, ammonium sulfate 0.25
q1L-glutamic acid-containing MEM amino acid 50-fold concentrated solution 2.0d.

0.5M phosphate buffer (1) 117.5) 20 d, 7
．． 5% Sodium Bicarbonate 1.3. The cells were inoculated at W/100 mf and cultured at 37°C for 3 days. The presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was determined as MIC.
(we).

The results are shown in Table-1.

(The following is a blank space) Table 1 ■ Using mice experimentally infected with Candida albicans 0N-28, the therapeutic effects of oral administration of the compounds of the present invention were measured.

Candida albicans 0N-283, 9 x 106 cells/mouse were injected into the tail vein of ICR male mice (body weight 19-21 g), 5 mice per group, to induce infection. Two hours after infection, 0.1 mg of the 9 test compounds per mouse was orally administered once, and the mice were observed for 10 days to see if they were alive or dead, and the relative therapeutic index was determined from the average survival days.

The results are shown in Table-2.

In addition, Table 2 shows the relative therapeutic coefficient of the test compound when the average survival days of ketoconazole is set as 100.

Table 2 [Effects of the Invention] As is clear from the above, it can be seen that the compound of the present invention exhibits extremely excellent pharmacological effects and is a highly safe compound.

(The following is a blank space) [Examples] Reference examples and examples are given to roughly explain the present invention in detail, but the present invention is not limited thereto.

The carrier used in column chromatography is silica gel manufactured by Merck & Co., Ltd. [Kieselgel 60, Art, 77].
34(niselgel 60.^rt, 7734
I used the moon.

The mixing ratio in the elution solvent depends on the volume ratio.

Furthermore, in the text and tables, the brackets [ ] indicate recrystallization solvents, and the following abbreviations have the following meanings.

Me: Methyl, Et: Ethyl, DEE Nidiethyl ether, ACOEt: Ethyl acetate Reference Example 1 Zinc 820#Ig and 2.5 g of ethyl 2-bromobutyrate
was suspended in 20 ml of dry tetrahydrofuran, and then 2-chloro-2-14' was suspended in 20 ml of dry tetrahydrofuran.
- A solution containing 2.0'j of difluoroacetophenone is added dropwise under reflux. Then, after reacting under reflux for 4 hours, insoluble materials were removed and the solvent was distilled off under reduced pressure.

Add 50Id of ethyl acetate to the residue! Add 50 liters of water and adjust the pH to 2.0 with 2N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography (elution solvent: n-hexane:toluene = 1; 2) to obtain oily ethyl = 3
- (2,4-difluorophenyl)-3,4-epoxy-2゜2-dimethylbutylade 2.1 g (yield 74
%).

IR) cm-';2960.1730.16
10.1260.1150 Similarly, remove one of the diastereomers of ethyl-4-chloro-3-(2°4-difluorophenyl)-2-fluoro-3-hydroxybutylade.

Melting point: 70.0-73.0°C IR (KBr) cm-1: 3420.1740.1
610.1495.1220 Reference Example 2 Magnesium 2001n9 and methyl iodide 1.2g
Dry tetrahydrofuran 10- is added to the dry diethyl ether solution 7d containing methylmagnesium iodide prepared above at -10 to 0°C. Then -70~-60℃
Ethyl-4-chloro-3-(2゜4-difluorophenyl)-2-fluoro-3-hydroxybutylar-1-5
5 ml of dry tetrahydrofuran solution containing 00#Ig is added dropwise. Then, after reacting at 20 to 25° C. for 12 hours, the reaction solution was introduced into a mixed solvent of 30 parts of ethyl acetate and 30 parts of water, and the pH was adjusted to 2.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography (elution solvent: toluene:ethyl acetate = 20:1) to obtain oily 1-chloro-2-(2,4-difluorophenyl)-3-fluoro-4- Methyl-2,4-bentanediol 280
ml (yield 58%).

IR) cm”; 330.1605.14
90.1410.1260 Similarly, ethyl, =a-
(2,4-difluorophenyl)-3,4-1boxy-
2,2-dimethylbutyler! - to oily 4- (2
,4-difluorophenyl)-4,5-epoxy-2,
'3゜3-trimethyl-2-pentanol was obtained.

IR) cm-1; 3470.2970.16
10.1495.1100 Reference Example 3 1-[1-(2,4-difluorophenyl)-1-hydroxy-2-(11-1-1,2,4-triazol-1-yl)ethyl]cyclopropane 1-carboxaldehyde and iodide 1,1°2.2,3,3.3-
Reference example 2 using hebutafluoropropylmagnesium
1-[1-(2,4-difluorophenyl)-1-hydroxy-2-(IH-1,2,4
-triazol-1-yl)ethyl]-1-(2,2,
3°3.4,4.4-heptafluoro-1-hydroxypentyl)cyclopropane was obtained.

Melting point: 136.0-140.0'C In (KBr) cm-1: 3345.1620.1
500.1425.1350 Reference Example 4 2.52d of dimethyl sulfoxide and 1.6d of acetic anhydride
1-[1-(2,4-difluorophenyl)-1-hydroxy-2-(IH-1,2,4
-1-riazol-1-yl)ethyl]-1-(2,2
,3,3,4,4,4-heptafluoro-1-hydroxypentyl) cyclopropane (420 mg) was added,
React at 25°C for 2 hours.

After the reaction is complete, add 20 parts of water and 20 parts of ethyl acetate to the reaction solution.
into a mixed solvent. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (elution solvent: toluene:ethyl acetate-5:1).
If purified by
, 4-triazol-1-yl)ethylcocyclopropyl)-2°2.3,3.4,4.4-hebutafluorobutanone iiomy (yield 26%).

Melting point: 122.5-123.5°C IR (KBr) cm-': 3100.1700.1
600.1490.1210 Reference Example 5 Diisopropylamine 1.829 and n-butyllithium (1,5N n-hexane solution) 12. To 20 ml of a dry diethyl ether solution containing lythiinpropylamide prepared from Od, 1.589 g of ethyl acetate was added dropwise at -75 to -65°C, and the mixture was allowed to react at the same temperature for 15 minutes. Then, at -75 to -65°C, 10 d of a dry tetrahydrofuran solution containing 2.08 g of 1-(2,4-difluorophenyl)-2-(IH-1,2,4-triazol-1-yl)ethanone was added dropwise. After that, the temperature was raised to 20°C over a period of 4 hours. After the reaction is completed, the reaction solution is introduced into a mixed solvent of 507 d of ethyl acetate and 50 d of water. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography (elution solvent: chloroborum:methanol = 100:1) to obtain oily ethyl-3-(2,4-difluorophenyl)-3-hydroxy-4-(IH- 1,2,4-triazole-1-
1.839 (yield: 66%) of butyrad (yield: 66%) is obtained.

IR) cm-'; 3400.1720.1
605.1490.1260 Compounds shown in Table 3 were obtained in the same manner.

1.32 g of 1,2,4-triazole and 2.63 g of anhydrous potassium carbonate were suspended in 20 ml of acetone.
2.0 g of bromo-1-(5-chloropyridin-2-yl)ethanone hydrobromide is added in portions under reflux. Then, after reacting for 0.5 hour under reflux, insoluble materials were removed and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (elution solvent; toluene:ethyl acetate:methanol=30:10:1) to obtain 4-
(5-chloropyridin-2-yl)-4-hydroxy-
5-(1H-1,2゜4-triazol-1-yl)-
380 mg (yield 21%) of 2-pentanone are obtained.

Melting point; 103.5-105.5°C 1R (KBr>cm-1; 3450.1685.1
445.1360 Example 1 310 mg of magnesium and 1.82 g of methyl iodide
Ethyl 3-(2,4-difluorophenyl)-3-hydroxy-4-(11(-1,2, 4-triazole-1-
Il) Butilade 1. After dropping 5 Inl of dry Te1-Rahydrofuran solution containing Oq, the temperature was raised to 20°C over 4 hours. After the reaction is complete, the reaction solution is diluted with 201d of ethyl acetate.
1 and 20 rd water, and β
Adjust to 1-f2.0. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (elution solvent; chloroform:methanol = 1
00:1), 2-(2,4-difluorophenyl)-4-methyl-1-(1H-1,2,.4-triazol-1-yl)-2,4-bentanediol 2
70 m5 (yield 28%) is obtained.

Melting point: 177.5-178.5°C IR (KBr) cm”: 3300.1600.1
5B5.1500.1480 Examples 2 to 14 In the same manner as in Example 1, the compounds shown in Table 4 were obtained.

(Left below) Example 15 4-(5-chloropyridin-2-yl)-4-hydroxy-5-(1H-1,2,4-triazol-1-yl)-2-pentanone and methylmagnesium iodide 2-(5-chloropyridin-2-yl)-4-methyl-1-(IH-1', 2.
4-triazol-1-yl)-2,4-bentanediol was obtained. This compound was roughly treated with a 2N hydrogen chloride-dioxane solution to give the dihydrochloride salt.

IR (Br) cm-'; 3150.1500.
1445.1355 Example 16 1-(1-[1-(2,4-difluorophenyl)-
1-Hydroxy-2-(IH-1,2,4-triazol-1-yl)ethylcocyclopropyl)-2,2,3
, 3,4,4,4-heptafluorobutanone and methylmagnesium iodide in the same manner as in Example 1.
2- (1-[1-(2,4-difluorophenyl)-
1-Hydroxy-2-(1H-1,2,4-triazol-1-yl)ethylcocyclopropyl)-3,3゜4
．． 4,5,5.5-hebutafluoro-2-pentanol was obtained.

Melting point: 145.5-147.5°C IR (KBr) cm-1: 3400.1610.1
495.1415.1335 Example 17 1-'70rho2-(2,4-difluorophenyl)
After dissolving 280 mg of -3-fluoro-4-methyl-2,4-bentanediol in 10 d of N,N-dimethylformamide, 210 mg of anhydrous potassium carbonate and 1,
Add 110 mg of 2.4-triazole and heat to 70-80°C.
After reacting for 5 hours, the solvent was distilled off under reduced pressure. Add 20 ml of ethyl acetate and 20 ml of water to the resulting residue,
Adjust the pH to 2°0 with 2N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography (elution solvent: chloroform:methanol-20:1) to obtain oily 2-(2,4
-difluorophenyl)-3-fluoro-4-methyl-
1-(IH-1,2,4-triazol-1-yl)-
2,4-bentanediol is obtained. Further, this compound was treated with a 2N hydrogen chloride-dioxane solution to give a hydrochloride salt of 160%.
mg (yield 46%).

Melting point: 192.0-195.0°C IR (Br) cm-1: 3450.1615.1
495.1420.1120 Example 18 1-chloro-2-(2,4-difluorophenyl)-3
-Similar to Example 17, using ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2°2-dimethylbutylade in place of fluoro-4-methyl-2,4-bentanediol. and 2-(2,4-difluorophenyl)-3,3,4-trimethyl-1-(1H
-1,2°4-triazol-1-yl)-2,4-bentanediol was obtained.

Melting point: 126.5-127.0°C IR (Br) cm-1: 3450.1615.14
95.1145.1095 Example 19 Dissolve 11 g of 2-(2-methoxyphenyl)-3,4-dim-1-yl)-2,4-bentanediol 500I in methylene chloride 207, and dissolve ethanethiol at -5 to 0°C. Add 1.0g and aluminum chloride, 1.099% of rum,
Stir the reaction at 0-5°C for 3 hours. After the reaction is completed, the reaction solution is introduced into a mixed solvent of 20 parts chloroform and 20 parts water. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (elution solvent:
If purified with chloroform:methanol=50:1),
2-(2-hydroxyphenyl)τ3,4-dimethyl-1
-(1)-1-1,2,4-triazol-1-yl)
-2゜4-bentanediol 1γOmg (yield 36%
).

Melting point: 180.0-161.0°C IR (Br) cm-1; 3230.1515.1
450.1365 Example 20 3.4-dimethyl-2-(pyridin-3-yl)-1-
(IH-1,2,4-triazol-1-yl)-2,
00 mg of 4-pentanedilua in 7 m of chloroform
- Chloroperbenzoic acid (purity 88%)
Add 550 mg and react at 15-20°C for 12 hours. After the reaction is complete, the reaction solution is subjected to column chromatography (
Elution solvent; chloroform:methanol = 20:1). yl)-2,4-bentanediol 650
mFj (yield 88%) is obtained.

Examples 21 and 22 3.4-dimethyl-2-(1-oxidepyridine-3-
yl)-1-(IH-1,2,4-triazole-1-
yl)-2,4-bentanediol (640 mg) was dissolved in 6.4 d of chloroform.

Add 290 mg of N-dimethylcarbamoyl chloride and react at 15 to 20°C for 12 hours. Then, 260 mg of trimethylsilyl cyanide was added and the mixture was heated at 15-20°C.
Let it react for 12 hours. After the reaction is completed, the reaction solution is purified by column chromatography (elution solvent: chloroform:methanol = 50:1) to obtain 2-(6-diatupyridin-3-yl)-3,4-dimethyl-1-(1H- 1,
501 IIg (yield: 8%) of 2,4-triazol-1-yl)-2,4-bentanediol is obtained.

Melting point: 204.0-205.0°C [ACOEt-D
EEIIR (KBr) cm”: 3120.15'
80,1495.1435.1305 If the elution continues, 2-(2-cyanopyridin-3-yl)-3,4
-dimethyl-1-(11-f-1,2,4-triazol-1-ylcin-2゜4-bentanediol 6omy
(yield 9%).

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ “In the formula, R^1 is an optionally substituted aryl or a heterocyclic group bonded via a carbon atom in the ring; R^
2 is a hydrogen atom, a fluorine atom, an alkyl or cycloalkyl group; R^3 is a hydrogen atom, an alkyl or cycloalkyl group; or R^2 and R^3 are formed together with the carbon atom to which they are bonded cycloalkyl ring ;R^
4 and R^5 are the same or different and represent an optionally substituted alkyl, cycloalkyl, alkenyl, aryl, or a heterocyclic group bonded via a carbon atom in the ring. Triazole derivatives and salts thereof.