JPH072802A - Production of optically active triazole derivative - Google Patents

Abstract

PURPOSE:To separate optically active isomers of a racemic triazole derivative useful as an antimycotic agent in high efficiency by using an optically active camphorsulfonic acid or a column for the separation of optically active isomers as optical resolution means. CONSTITUTION:A mixture of a diastereomer salt of a triazole derivative of the formula and an optically active camphorsulfonic acid is formed by reacting a racemic triazolyl derivative of the formula (R<1> and R<2> are H, lower alkyl or together form lower alkylene; R<3> is lower alkyl; n is 0-2; R<1> and R<2> are not H at the same time) with an optically active camphorsulfonic acid. An optically active isomer of the triazole derivative is produced by crystallizing exclusively one of the diastereomer salt from the mixture and desalting the product. As an alternative method, the racemic compound of the formula is subjected to column chromatography with a column packed with an optically active stationary phase to effect the optical resolution of the compound. An optically active compound having high purity can be produced by this process on an industrial scale at a low cost.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an optically active triazole derivative useful as an antifungal agent.

[0002]

BACKGROUND OF THE INVENTION Many azole compounds have excellent antifungal activity, some of which are various tinea, tinea, psoriasis, cutaneous candidiasis, fungal meningitis, fungal respiratory infection. It is widely used as a therapeutic agent for diseases such as infectious diseases, fungal diseases, and urinary mycosis. By the way, the following general formula (1)

[0003]

[Chemical 3]

[Wherein R¹And R²Is a hydrogen atom
Represents a lower alkyl group, or R ¹And R²Together
May form a lower alkylene group. R³Is low
It represents an alkyl group, and n represents an integer of 0 to 2. However,
R¹And R²Are not both hydrogen atoms. ]
Triazole derivatives have excellent antifungal activity
It is known that Also, this triazole derivative
The optically active form (1) is stronger than its racemic form.
It has an antifungal action and is highly safe, so
It is known to be useful as a therapeutic agent for mycosis (special
Kaihei 3-223266). In particular, triazole
R of the conductor (1)¹, R², R³Are both methyl groups
And the (−) form of the compound where n is 2 is useful.

As a method for producing the optical isomer of the triazole derivative (1), two diastereomers are prepared by reacting a 2-alkylthioacetophenone derivative with an optically active sulfinyl compound such as S (-) methyl-p-tolyl sulfoxide. Mer mixture, an optically active substance is obtained from this mixture by silica gel column chromatography, the optically active substance is further oxidized, acetyl chloride is reacted with sodium iodide, and then epoxidation is performed, followed by reaction with triazole. Is known (Japanese Patent Application Laid-Open No. Hei 3
-223266 publication).

[0006]

However, the method for producing an optically active substance of the triazole derivative (1) is industrially difficult because the separation efficiency of two diastereomers, which is an intermediate step, is poor and the production step is long. It was inevitable as a disadvantageous production method. Therefore, an object of the present invention is to provide a method for industrially producing a highly pure optically active isomer of the triazole derivative (1).

[0007]

Therefore, the present inventors have made various studies on the optical resolution of the racemate of the triazole derivative (1) which can be industrially advantageously produced, and have been widely known as an optical resolving agent. The optically active compound could not be isolated even with the use of tartaric acid derivatives, etc., but the optically active compound can be efficiently isolated by using optically active camphorsulfonic acid, and the optical resolution using a column for separation of optical isomers. However, they have found that the optically active substance can be efficiently separated, and have completed the present invention.

That is, in the present invention, the optically active camphorsulfonic acid is reacted with the racemate of the triazole derivative represented by the general formula (1), and the diastereomer of the triazole derivative (1) and the optically active camphorsulfonic acid is reacted. Forming a mer salt mixture, and then crystallizing only one diastereomer salt from the mixture, followed by desalting, which provides a method for producing an optically active form of the triazole derivative (1). Is.

Further, the present invention is characterized in that the racemate of the triazole derivative represented by the general formula (1) is subjected to chromatography using a column packed with an optically active stationary phase. A method for producing an optically active substance is provided.

Triazole derivatization used in the method of the present invention
In the general formula (1) representing the body, R¹, R ²And R³Indicated by
Examples of the lower alkyl group include a straight chain having 1 to 6 carbon atoms or
Is a branched chain alkyl group, specifically methyl
Group, ethyl group, n-propyl group, isopropyl group, n-
Butyl group, isobutyl group, sec-butyl group, tert
-Butyl group, n-pentyl group, n-hexyl group, etc.
And a methyl group is preferable in each case. Also, R¹and
R²The lower alkylene group formed by
An alkylene group having a number of 2 to 5, for example, an ethylene group, a trimer
Examples thereof include a ethylene group and a tetramethylene group. Such
A hydroxyl group is bonded to the lyazole derivative (1).
Carbon atom, R¹And R²Is the carbon atom to which
There are isomers based on sulfur atoms, but hydroxyl groups are
Except for optical isomers based on the asymmetry of the carbon atoms attached
Easily by the method described in JP-A-3-223266
It can be separated into stereoisomers. Optical resolution by the method of the present invention
The reason for this is that the hydroxyl group,
It is a racemic body based on the asymmetry of existing carbon atoms. Triazo
The racemate of the diol derivative (1) is described in, for example, JP-A-3-2
It can be easily manufactured according to the method described in Japanese Patent No. 23266.
You can

Examples of the optically active camphorsulfonic acid which is an optical resolving agent used in the method of the present invention include, for example, optically active camphorsulfonic acid which may be substituted with a halogen atom or a salt thereof, specifically (+)-camphor. −
10-sulfonic acid, (-)-camphor-10-sulfonic acid, (+)-3-bromocamphor-8-sulfonic acid, (+)-3-bromocamphor-10-sulfonic acid, (-)-3- Bromocamphor-8-sulfonic acid,
(−)-3-bromocamphor-10-sulfonic acid,
(+)-3-Bromocamphor-8-sulfonic acid ammonium salt, (−)-3-bromocamphor-8-sulfonic acid ammonium salt and the like can be mentioned, among which (+)-3.
-Bromocamphor-8-sulfonic acid, (-)-3-bromocamphor-8-sulfonic acid, (+)-3-bromocamphor-8-sulfonic acid ammonium salt, (-)-
3-Bromocamphor-8-sulfonic acid ammonium salt is preferred.

The reaction between the racemate of the triazole derivative (1) and the optically active camphorsulfonic acid is carried out in a solvent suitable for crystallizing only one of the diastereomeric salts from the diastereomeric salt mixture produced by this reaction. It is preferable to carry out. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and t-butanol; hydrocarbons such as benzene, toluene, xylene, and ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether. ;
Halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; acetone, acetonitrile, dimethylformamide, dimethylsulfoxide and the like.

In this reaction, 0.5 to 1 mol of optically active camphorsulfonic acid is used per 1 mol of the racemate of the triazole derivative (1), the compound is dissolved in the above solvent, and the temperature is from room temperature to the boiling point of the solvent. Done in. By this reaction, a mixture of an optically active substance of the triazole derivative (1) and a diastereomer salt of optically active camphorsulfonic acid is produced.

In order to crystallize only one of the diastereomeric salts from this diastereomeric salt mixture, the difference in the solubility of the diastereomeric salts in the solvent is utilized. For example, by cooling the reaction mixture. Further, it is preferable to add a small amount of seed crystals having high optical purity prepared in advance. Further recrystallization of one of the precipitated diastereomeric salts improves the optical purity.

Desalination of the obtained diastereomeric salt is carried out, for example, by treating in a mixed solution of an organic solvent and an aqueous alkaline solution. By doing so, the optically active substance of the target triazole derivative (1) is transferred to the organic solvent, and thus the target substance can be easily separated and purified from the organic layer. The organic solvent used here is preferably ethyl acetate, chloroform, methylene chloride or the like. As the alkaline aqueous solution, an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or the like is used.
Further, the separation and purification of the target substance from the organic layer may be carried out, for example, by recrystallization, and as the recrystallization solvent, water, methanol, ethanol, propanol, isopropanol,
Ether, isopropyl ether, tetrahydrofuran, dioxane and the like can be used alone or as a mixed solvent.

Further, the optically active substance of the triazole derivative (1) is (+)-or (-)-3 as an optical resolving agent.
By using -bromocamphor-8-sulfonic acid ammonium salt, it is more industrially advantageously produced.
This method is particularly suitable for (-)-3-methyl-3-methylsulfonyl-1- (1,2,4-triazol-1-yl).
Preference is given to using it for the production of 2- [4- (trifluoromethyl) phenyl] butan-2-ol.

That is, (-)-3-bromocamphor-8- in the presence of racemic compound such as sulfuric acid and methanesulfonic acid.
Optically active salt using ammonium sulfonate, that is, (−)-3 of (−) form of triazole derivative (1)
By forming -bromocamphor-8-sulfonate, followed by desalting, purification treatment and the like, the triazole derivative (1) (-) having high optical purity can be easily obtained in high yield. In addition, (+)-3-bromocamphor-
It is also possible to use ammonium 8-sulfonate, in which case (+)-3-bromocamphor-8-sulfonate of the (−) form of the triazole derivative (1) is produced, and in the same manner as above. By the treatment, the (−) form of the triazole derivative (1) having high optical purity can be easily obtained in high yield. These optically active salts can be formed in a solvent such as alcohol (methanol, ethanol, isopropyl alcohol, etc.) under the condition of the temperature between about 0 ° C and about 30 ° C. Ammonium ion is sulfuric acid,
By coexisting with methanesulfonic acid or the like, it can be removed as an ammonium salt of the acid. Desalting of optically active salts
For example, it is carried out by using an alkali such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate or ammonium or an organic base such as triethylamine. For the purification, a method known per se such as a recrystallization method can be adopted. In addition,
When crystallizing an optically active salt, the (−)-3-bromocamphor-8-sulfonate of the (−) form of the high-purity triazole derivative (1) or the (−) of the triazole derivative (1) is used. (+)-3-Bromocamphor-8 in the body
-Preference is given to adding sulfonate seed crystals.

(+)-3-Bromocamphor-8-sulfonic acid ammonium salt as an optical resolving agent, and (+)-form (+)-3-bromocamphor of the high-purity triazole derivative (1) as a seed crystal. By using -8-sulfonic acid salt, (+)-form (+)-3-bromocamphor-8-sulfonic acid salt of triazole (1) is obtained as crystals, and the triazole derivative (1) of the triazole derivative (1) is obtained from the mother liquor. Since crude crystals of the (-) form are obtained, (+)-camphor-10-sulfonic acid is used as a crystallization agent, and (-) form of the (-) form of the high-purity triazole derivative (1) is used as a seed crystal. By using +)-10-camphor sulfonate, the (+)-camphor-10- of the (−) form of the triazole derivative (1) having high optical purity is obtained.
A sulfonate salt is obtained. By treating this salt in the same manner as above, the free triazole derivative (1) (-) form is obtained in high yield.

Next, a method of using a column for separating optical isomers will be described. Examples of the optically active stationary phase include synthetic optically active polymers, natural polymers, metal complexes of amino acids, and the like, and silica gel coated with a cellulose derivative is preferable. As the column packed with the silica gel coated with the cellulose derivative, a commercially available product such as a column for chiral cell OJ optical isomer separation (manufactured by Daicel Chemical Industries, Ltd.) can be used. Liquid chromatography is preferred as the format of chromatography. In this case, the eluent as the mobile phase can be, for example, hexane-ethanol-diethylamine, hexane-isopropanol or the like.

[0020]

According to the method of the present invention, an optically active substance of the triazole derivative (1) useful as a therapeutic agent for various fungal diseases can be produced easily and industrially advantageously.

[0021]

EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 (-)-3-Methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
Synthesis of (trifluoromethyl) phenyl] butan-2-ol [hereinafter referred to as the "target (-) form"]: (1) (±) -3-methyl-3-methylsulfonyl-1
-(1,2,4-triazol-1-yl) -2- [4
To 100 g of-(trifluoromethyl) phenyl] butan-2-ol was added 1.8 l of isopropanol, and the mixture was heated to 65 ° C.
Dissolved under stirring. At the same temperature, 0.61 of an isopropyl alcohol solution containing 82.5 g of (+)-3-bromocamphor-8-sulfonic acid was added, and the mixture was stirred at 80 ° C for 30 minutes. Fifty
After allowing to cool to ℃, seed with high-purity seed crystals and
Let stand for days. The precipitated crystals were collected by filtration, washed with 0.2 l of isopropanol, and dried to obtain (+)-of the desired (-) form.
98.3 g of 3-bromocamphor-8-sulfonate
Obtained (optical purity 53.8% ee).

(2) 2 liters of isopropanol was added to the obtained salt of the target (-) form, and the mixture was stirred and dissolved at 80 ° C for 40 minutes, inoculated with a highly pure seed crystal, and allowed to stand at 25 ° C for 2 days. The precipitated crystals were collected by filtration, and 0.2 liter of isopropanol
After washing with water and drying, 70.0 g of (+)-3-bromocamphor-8-sulfonate of the objective (-) form was obtained (optical purity 96.4% ee). Further, this salt was dissolved in 1.5 liter of isopropanol with heating, and the same operation was performed to obtain 62.2 g of (+)-3-bromocamphor-8-sulfonate of the objective (-) form (optical purity 99.5% e.
e. ).

(3) A mixture of the above salt, 0.7 l of ethyl acetate and 0.25 l of 10% potassium carbonate was stirred, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from 40% ethanol to obtain 25.9 g of the target (-) form. Optical purity 99.5% e.
e. , Melting point 145 to 147 ° C., [α] _D ²⁵ −9.4 °
(C = 0.5, acetone)

Example 2 (±) -3-methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
(Trifluoromethyl) phenyl] butan-2-ol 200 mg, (+)-camphor-10-sulfonic acid 6
3 ml of isopropanol was added to 1.6 mg and heated,
Dissolved. Seed crystals were inoculated and left at room temperature overnight. The precipitated crystals were collected by filtration, washed with 1 ml of isopropanol, and then dried to obtain (+)-camphor-10 of the desired (-) form.
80 mg of sulfonate were obtained (optical purity 82.0%
e. e. ). This salt was recrystallized and then desalted in the same manner as in Example 1 to obtain a highly pure target (-) form.

Example 3 (±) -3-methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
The (trifluoromethyl) phenyl] butan-2-ol was used as a mobile phase (hexane: ethanol: diethylamine = 800 :) using a chiralcel OJ optical isomer separation column.
200: 1) to separate the respective optical isomers, and the target (-) isomer (optical purity 99% ee) and (+)-3-
Methyl-3-methylsulfonyl-1- (1,2,4-triazol-1-yl) -2- [4- (trifluoromethyl) phenyl] butan-2-ol (optical purity 99%
e. e. ) Got.

Example 4 (±) -3-methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
10 g of (trifluoromethyl) phenyl] butan-2-ol and 6.3 g of (−)-3-bromocamphor-8-sulfonic acid ammonium salt were added to 100 ml of methanol.
Was dissolved in water, 1.33 g of concentrated sulfuric acid was added under water cooling, and methanol was distilled off under reduced pressure. Isopropanol 15 in the residue
Add 0 ml and dissolve by heating. After filtering off the insoluble matter,
Inoculation with (-)-3-bromocamphor-8-sulfonate of the objective (-) form of high purity is performed, and the mixture is allowed to stand at room temperature overnight. The precipitated crystals are collected by filtration and dried to obtain the desired (-) form (-)-
8.2 g of 3-bromocamphor-8-sulfonate was obtained as white crystals (optical purity 96% ee). When recrystallized from 82 ml of isopropanol, the optical purity was 99.5% e.p. e. (-)-3-Bromocamphor-8-sulfonate of the above objective (-) form 7.
8 g was obtained. This salt was suspended in 150 ml of water, made alkaline with potassium carbonate, extracted with ethyl acetate, washed with water and dried. After concentration, the residue was recrystallized from hydrous ethanol to obtain 4.1 g of the target (-) form as white crystals. Melting point 145-147 ° C, yield 82%. [Α] _D ²⁵
-10.7 ° (c = 0.5, acetone).

Example 5 (±) -3-methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
10 g of (trifluoromethyl) phenyl] butan-2-ol and 6.3 g of (+)-3-bromocamphor-8-sulfonic acid ammonium salt were added to 100 ml of methanol.
Was dissolved in water, 1.33 g of concentrated sulfuric acid was added under water cooling, and methanol was distilled off under reduced pressure. Isopropanol 15 in the residue
Add 0 ml and dissolve by heating. After filtering off the insoluble matter,
A high-purity (-)-form (+)-3-bromocamphor-8-sulfonate is inoculated and left overnight at room temperature. The precipitated crystals are collected by filtration and dried to give the desired (-) form (+)-
8.3 g of 3-bromocamphor-8-sulfonate was obtained as white crystals. Optical purity 53% e. e. . This was recrystallized twice from isopropanol to give an optical purity of 99.5% e.p. e. (+)-Of the above purpose (-) body
5.5 g of 3-bromocamphor-8-sulfonate was obtained. This salt was treated in the same manner as in Example 4 to obtain the objective (-).
2.8 g of body was obtained. Melting point 145 to 147 ° C, yield 56
%. [Α] _D ²⁵ -10.8 ° (c = 0.5, acetone).

Example 6 (±) -3-methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
9.1 g of (trifluoromethyl) phenyl] butan-2-ol and 5.7 g of (+)-3-bromocamphor-8-sulfonic acid ammonium salt were added to 90 ml of methanol.
Was dissolved in water and 1.21 g of concentrated sulfuric acid was obtained under water cooling, and then methanol was distilled off under reduced pressure. Isopropanol 136 on residue
Add ml and dissolve by heating. After filtering off the insoluble matter, highly pure (+)-3-methyl-3-methylsulfonyl-1
-(1,2,4-triazol-1-yl) -2- [4
Inoculate (+)-3-bromocamphor-8-sulfonate of-(trifluoromethyl) phenyl] butan-2-ol and leave at room temperature overnight. The precipitated crystals are collected by filtration,
When dried, (+)-3-methyl-3-methylsulfonyl-1- (1,2,4-triazol-1-yl) -2
-[4- (trifluoromethyl) phenyl] butane-2
7.1 g of (-)-3-bromocamphor-8-sulfonate of -ol was obtained as white crystals. Optical purity 9
9% e. e. . The crude (-) form 5.4 obtained from this mother liquor
g is dissolved in 80 ml of isopropanol, 3.3 g of (+)-camphor-10-sulfonic acid is added, and dissolved by heating. A high-purity (+)-form (+)-camphor-10-sulfonate was inoculated into this, and after standing at room temperature overnight, the precipitated crystals were collected by filtration and recrystallized from isopropanol to give an optical purity of 99.5. % E. e. Purpose of the above (-)
6.1 g of (+)-camphor-10-sulfonate of the body
was gotten. This salt was treated in the same manner as in Example 4 to obtain 3.6 g of the desired (-) form. Melting point 145-147 ° C, yield 79%. [Α] _D ²⁵ -10.8 ° (c = 0.5, acetone).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Nakazawa et al. 3-5-23-102 Hashigadai, Narita City, Chiba Prefecture (72) Inventor Hideaki Matsuda 2-29-8 Higashi Abiko, Abiko City, Chiba Prefecture Inventor Tadayuki Kuraishi 2-5-4 Kasumi, Narashino City, Chiba Prefecture (72) Minoru Tsuruta, Inoue, 955 Address, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture Yoshitomi Pharmaceutical Co., Ltd. Drug Discovery Research Center (72) Kazuyuki Kawasaki, Yoshitomi, Chikami-gun, Fukuoka Prefecture Machizai Ozawari 955 Address Yoshitomi Pharmaceutical Co., Ltd. Drug Discovery Research Center

Claims (2)

[Claims] 1. A compound represented by the general formula (1):[In the formula, R¹And R²Is a hydrogen atom or lower alk
Represents a radical or R ¹And R²Together with
A alkylene group may be formed. R³Is a lower alkyl group
It shows and n shows the integer of 0-2. However, R¹And R²But
Neither becomes a hydrogen atom. ] Represented by
Optically active camphor sulfone as racemate of sol derivative
The triazole derivative and the optically active carboxylic acid are reacted with an acid.
Diastereomeric salt mixture with
Formed and then one diastereomer from the mixture.
It is characterized in that only the mer salt is crystallized and then desalted.
Process for producing optically active triazole derivative. 2. A compound represented by the general formula (1):[In the formula, R¹And R²Is a hydrogen atom or lower alk
Represents a radical or R ¹And R²Together with
A alkylene group may be formed. R³Is a lower alkyl group
It shows and n shows the integer of 0-2. However, R¹And R²But
Neither becomes a hydrogen atom. ] Represented by
The racemic sol derivative is packed with an optically active stationary phase.
Characterized by being subjected to chromatography using ram
A method for producing an optically active substance of the triazole derivative.