JPH0393775A - Production of threo-isomer - Google Patents

Abstract

PURPOSE:To obtain a threo-isomer of a triazole derivative having improved antimycotic activity by isomerizing an erythro-isomer of a triazole derivative with a base in water or a mixture of water and an organic solvent. CONSTITUTION:An erythro-isomer of a compound of formula (Ar is phenyl; Y is triazole or imidazole residue; R<1> and R<2> are lower alkyl; n is 0, 1 or 2) is isomerized by reacting with a base (e.g. NaOH) in water or in a mixture of water and an organic solvent (e.g. methanol) at a temperature between room temperature and the boiling point of the solvent for 0.5-10hrs. The amount of the solvent is 3-20 pts.wt. per 1 pt.wt. of the compound of formula (the sum of erythro-isomer and threo-isomer) and the concentration of the base is 0.1-10M based on water in the isomerization reaction.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention is directed to the general formula (1) (where Ar represents a substituted or unsubstituted phenyl group), which is known to be useful as an antifungal agent. , Y represents a triazole group or imidazole group, Rl and R! each represent a lower alkyl group, and n represents 0, 1 or 2). Concerning efficient manufacturing methods. [Prior art/problems to be solved by the invention] Since the compound represented by the general formula (1) has two asymmetric carbon atoms in its molecule, it exists in stereoisomers of threo and erythro forms. However, it is known that the threo form exhibits stronger antifungal activity.
Therefore, there is a long-awaited ability to selectively produce threo bodies. As a method for producing it, for example, the method shown by the following reaction formula A is known [Collection of Abstracts of the 8th Medicinal Chemistry Symposium (1986), No. 9]. Anti-5Δ[k Anti-5Δ吏W (In the reaction formula, Ar and Y have the same meanings as above) In the method according to reaction formula A, the threo isomer can be selectively produced, but the general formula (1) In order to obtain the compound represented by , it is necessary to introduce a sulfur atom, which requires several steps, which lengthens the manufacturing process, and therefore there is a problem that it is not an economical or even industrial manufacturing method. In addition, a production method shown in Reaction 2B below, which uses a compound into which a sulfur atom is introduced from the beginning, is also known (Collection of Abstracts of the 8th Medicinal Chemistry Symposium (1988), p. 9). (In the reaction formula, A r % Y has the same meaning as above) In the method of reaction 2B, the erythro form can be selectively produced by selecting the reaction conditions, but the threo form can be selectively produced. However, even if suitable conditions are selected, the threo isomer and the erythro isomer can only be obtained in a 1:1 mixture. Therefore, although the method shown in Reaction Formula B has a short manufacturing process, in order to be an economical manufacturing method, it is necessary to convert the erythro isomer to the threo isomer and reuse it. Therefore, an object of the present invention is to provide a method for producing the threo isomer from the erythro isomer of the compound represented by the general formula (1). [Means for solving the problem] It is well known that compounds with such a structure are susceptible to isomerization because the hydrogen atom bonded to the asymmetric carbon adjacent to the sulfur atom can be extracted by a base. However, according to the experiments conducted by the present inventors, the erythro form of the compound represented by the general formula (1) is a base such as DBU (1.
8-diazabicyclo(5.4.0)-7-undecene)
When , n-butyllithium or sodium hydride-dimethylsulfoxide was reacted, the hydrogen atom of the hydroxyl group was first removed to form an alkoxide, so the decomposition reaction shown in Reaction Formula C took priority and the isomerization reaction hardly progressed. ．． (1) (Ninaka, ArSY, R', Rtomi and n have the same meanings as above.) Against this background, the present inventors conducted various studies on the reaction conditions of the isomerization reaction. When a base is applied to the erythro form of the compound represented by the general formula (1), if a mixed solvent of water and an aqueous solvent or water is used as the solvent, this decomposition reaction is suppressed and the isomerization reaction becomes preferential. We found that the process progresses to Furthermore, the present inventors found that in this isomerization reaction, the erythro isomer is produced at the same time as the threo isomer, and in the solution state, there is an equilibrium at a certain mixing ratio, and this ratio is approximately 2 to It was found that there was a 5-fold excess. Furthermore, since the solubility of the compound represented by general formula (1) in a solvent is lower for the threo form than for the erythro form, the threo form will separate as crystals during the isomerization reaction under the conditions specified in the present invention. It was discovered that the equilibrium in the solution is shifted, and as a result, almost all of the erythro form is converted to the threo form.The present invention has been completed based on the above new findings, and the gist thereof is as follows. , a compound characterized in that the erythro form of the compound represented by general formula (1) is reacted with a base in a mixed solvent of water and an organic solvent or in water (
1) is a method for producing an erythrobody.

The method of the present invention will be explained in more detail below. In this specification, each symbol preferably has the following meaning.

The lower alkyl group is a straight-chain or branched alkyl group, and specific examples thereof include lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, probyl, isopropyl, and butyl groups. Examples of the substituents of the substituted phenyl group include halogen atoms such as chlorine atom, bromine atom, and fluorine atom, and lower alkoxy groups such as methoxy and ethoxy (preferably carbon atoms 1 to 4).
), lower alkyl groups as mentioned above such as methyl, ethyl, proyl, t-butyl, yakuchi lower alkyl groups such as trifluoromethyl, tetrafluoroethyl, halo lower alkoxy groups such as trifluoromethoxy (preferably carbon number 1 to 4), phenyl group, phenoxy group, benzyl group, penzyloxy group, Yaguchi penzyloxy group, and nitro group. Examples of substituted or unsubstituted phenyl groups include phenyl group, 2-. 3- or 4-chlorophenyl group, 2.4- or 2.6-dichlorophenyl group, 2.3- or 4-fluorophenyl group, 2.4
- or 2,6-difluorophenyl group, 23-t4
! 4-promophenyl group, 2-chloro-4-fluorophenyl group, 2-fluoro-4-chlorophenyl group, 2-
chloro-6-fluorophenyl group, 2-, 3- or 4
-methoxyphenyl group, 2,4-dimethoxyphenyl group, 2-, 3- or 4-ethoxyphenyl group, 2-. 3
- or 4-nitrophenyl L 2-chloro-5-nitrophenyl group, 2-, 3- or 4-methylphenyl group, 2,4-dimethylphenyl L 2-, 3- or 4-
t-butylphenyl group, 2-, 3- or 4-trifluoromethylphenyl group, 2-3- or 4-trifluoromethoxyphenyl group, 2-. 3- or 4-(1
．． 1.2.2-tetrafluoroethyl)phenyl group, 2
-fluoro-4-methoxyphenyl group, 2-methoxy-
4-fluorophenyl group, 2-methoxy-4-chlorophenyl group, 2-methoxy4-fluorophenyl group, 2
3- or 4-phenoxyphenyl group, 2-. 3- or 4-phenylphenyl group (2-, 3-4 or 4-biphenylyl group), 2-, 3- or 4-henylphenyl group, 2-. 3- or 4-penzyloxyphenyl group, 2
−． 3- or 4-(4-chloro or 4-fluorobenzyloxy) phenyl group. Examples of the triazole group include a 1,2.4-} riazole group and a 1,3.4-} riazole group. In the present invention, a mixed solvent of water and an organic solvent or water and a base are added to the erythro form of the compound represented by the general formula (1), and the mixture is preferably kept warm at a temperature usually between room temperature and the boiling point of the solvent. While stirring the isomerization reaction, the resulting threo isomer is precipitated as crystals to obtain the threo isomer in high yield. The starting material of the present invention is the erythro compound of the compound represented by the general formula (1), but the starting material may be a mixture of the erythro compound and the threo compound.

Examples of organic solvents include alcoholic solvents such as methanol, ethanol, isopropanol, and ethylene glycol;
Examples include ether solvents such as tetrahydrofuran and dimethoxyethane, and any mixed solvents thereof. When a mixed solvent of water and an organic solvent is used as a solvent, there is no particular restriction on the mixing ratio of the two, but it is preferable to use more water than the organic solvent. In particular, in order to obtain the threo isomer in good yield by isomerizing the erythro isomer and precipitating the threo isomer from the resulting mixture of the erythro and threo isomers to shift the equilibrium in the solution, water is used as the sole solvent. When using a mixed solvent of water and an ai medium, it is particularly preferable to use water in an amount equal to or more than the organic solvent, preferably twice or more, and more preferably three times or more. preferable. The amount of solvent used does not have a large effect on the isomerization reaction, but it is usually 3-3 to
It is preferable to use 20 times the amount by weight in terms of yield and operability. The base used in the present invention is preferably an inorganic base, such as an alkali metal hydroxide, carbonate or other basic salt, or an alkaline earth metal hydroxide, carbonate or other base. Examples include basic salts of More specifically, examples include lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, rubidium carbonate, cesium carbonate, Examples include sodium phosphate, potassium phosphate, sodium acetate, sodium borate, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium carbonate, etc. From an industrial standpoint, sodium hydroxide and potassium hydroxide are preferred examples. It can be mentioned as follows. The isomerization reaction proceeds equally well whether the base is dissolved in water in advance and acts as an aqueous solution of the base or separately from the solvent. The concentration of the base, expressed as a concentration relative to water during the isomerization reaction, is preferably in the range of 0.1 to 10M, particularly preferably in the range of 0.2 to IM.

The temperature during the isomerization reaction is usually in the range of room temperature to the boiling point of the solvent, but in terms of reaction rate, it is preferable to heat it to 50"C or higher. ~1
It is carried out for 0 hours, preferably 2 to 8 hours. After completion of the reaction, the threo form of the compound represented by formula (1) -a can be isolated by a method commonly used in organic synthesis. That is, for example, after the completion of the reaction, the grown crystals may be filtered as they are, or after the pH of the reaction solution is adjusted to below 10, or after the organic solvent is removed if an organic solvent is used as the reaction solvent. The threo form of the compound represented by formula (1) can be obtained by filtering the precipitated crystals. Of the erythro compound represented by the general formula ([), n
A compound in which n = 1 can be obtained by a known method from a compound in which n = o, and a compound in which n = 2 can be obtained from a compound in which n = 0.1, for example, as disclosed in JP-A-61-85369 or JP-A-61-85369. It can be obtained according to the method described in Application No. 62331470. Among the compounds represented by the -S formula (!), examples in which the isomerization reaction proceeds particularly well include Ar being a 2,4-difluorophenyl group and Y being a 1.2. Examples include compounds in which Rl and Rχ are each methyl groups, and n is 2.

Although the case where a pure erythro form is used as the object of the isomerization reaction has been described above, a mixture of a threo form and an erythro form can also be isomerized in the same manner.

Furthermore, in the general formula (1), the threo isomer of a compound where n is l or 2 can be obtained by subjecting the erythro isomer or a mixture of the threo isomer and erythro isomer of the compound where n = 0 to an oxidation reaction, and then directly adding a base. It is also possible to convert the erythro isomer to the threo isomer by subjecting it to the isomerization reaction, which is the method of the present invention, and to extract only the threo isomer. In this case, only the threo isomer can be obtained as the final compound without separating the threo isomer and the erythro isomer during the reaction step shown in reaction 2B. Therefore, if the method of the present invention is used, the production ratio of the threo isomer and the erythro isomer will no longer be a problem, and it can be said that the method has extremely high industrial utility value.

[Effects of the present invention]

By using the method of the present invention, it becomes possible to reuse the erythro isomer of the compound (+), which was an unnecessary isomer in the past, as the threo isomer, and the threo isomer of the compound represented by the -S formula (1) can be reused as the threo isomer. It becomes possible to manufacture it industrially advantageously.

〔Example〕

The present invention will be described in more detail with reference to Examples below, but the present invention is not limited thereto.
In addition, it was confirmed by HPLC that the threo form obtained in each example corresponded to the standard product.

Example l 200 μl of (±)-erythro-2-(2.4-difluorophenyl)-3-methylsulfonyl-1-(1,2.4-triazol-1-yl)butan-2-ol was added with IN water. Add sodium oxide aqueous solution 2, and heat at 60℃ for 5 minutes.
The mixture was kept warm and stirred for an hour. After stirring at room temperature for 1 hour, the crystals were collected by filtration and added with 0.0% water. Twice with 2 ml and 0.0 methanol. Washed once for 2 d. By drying under reduced pressure, (±)-threo-2-(2.4-difluorophenyl)-3-methylsulfonyl-1-(1.2.4-triazole-1-
yl)butan-2ol 145a+g was obtained. Example 2 (±-threo-2 4-difluoro(±)-erythro-2-(2.4-difluorophenyl)-3-methylsulfonyl-1-(1,2.4-triazole-1
-yl) butan-2-ol (200 μl) and 1.0 μl of 1N aqueous sodium hydroxide solution. 5 m and methanol 0. 5
d was added and stirred at 60°C for 5 hours. 1 at room temperature
After stirring for an hour, the crystals were collected by filtration, and the water was 0.0%. 2 times at 2 m, cold methanol 0. Washed once for 2 d. By drying under reduced pressure, (±)1threo-2-(2.4-difluorophenyl)-3-methylsulfonyl-1-(1.2.
4- }Riazol-1-yl)butan-2-ol 1
I got 29■. Example 3 200 μl of (±)-erythro-2-(2.4-difluorophenyl)-3-methylsulfonyl-1-(1.2,4-triazol-l-yl)butan-2-ol was added with IN hydroxylation. An aqueous sodium solution iml and methanol lIIIl were added, and the mixture was stirred at 60°C for 5 hours. After stirring at room temperature for 1 hour, the crystals were collected by filtration and diluted twice with 0.2-liter of water.
Washed once with 0.2-ml of cold methanol. By drying under reduced pressure, (±)-1threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1,2
．． 79 µ of 4-triazol-l-yl)butan-2-ol was obtained. Example 4 200 μl of (±)-erythro-2-(2.4-difluorophenyl)-3-methylsulfonyl-1-(1,2.4-triazol-1-yl)butan-2-ol was added with IN water. Add 2 m of lithium oxide aqueous solution and heat at 60°C for 5 minutes.
Stir and keep warm for hours. After stirring at room temperature for 1 hour, the crystals were collected by filtration and added with 0.0% water. 2 times with 2 d, 1 time with 0.21 d of cold methanol
Washed twice. By drying under reduced pressure, (±)-threo-2-(2.4-difluorophenyl)-3-methylsulfonyl-1-(1.2.4- }riazol-l-yl)butan-2-ol I got 148■. Example 5 200 μl of (±)-erythro-2-(2.4-difluorophenyl)-3-methylsulfonyl-1-(1.2.4-triazol-l-yl)butan-2-ol was added with IN hydroxylation. Add potassium aqueous solution 2id and heat at 60℃ for 5 minutes.
Stir and keep warm for hours. After stirring at room temperature for 1 hour, the crystals were collected by filtration and added with 0.0% water. 2 times with cold methanol 0.2 d. Washed once for 2 d. By drying under reduced pressure, (±)1threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-(1,2,4-triazol-1-yl)butan-2-ol143■ I got it. Example 6 (± -threo2-1-difluorof(±)-erythro2-(2.4-difluorophenyl)-3-
To 200 μl of methylsulfonyl-1-(1,2.4-triazol-1-yl)butan-2-ol, 0.
Add 2 d of 2 N aqueous sodium hydroxide solution and heat at 60°C for 5
Stir and keep warm for hours. After stirring at room temperature for 1 hour, the crystals were collected by filtration and added with 0.0% water. 2 times with cold methanol 0.2 d. Washed once at 2 m. By drying under fIi pressure, (±)1threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-l-(1,2,4-triazol-1-yl)butan-2-ol 161 I got ■. Example 7 1.25 g of (±)-erythro-2-(2.4-difluorophenyl)73-methylthio-1-(1,2.4-triazol-1-yl)butan-2-ol and (
±) one-threo2-(2.4-difluoro-phenyl)-
Dissolve a mixture of 0.05 g of 3-methylthio-1-(1,2.4-}lyazol-1-yl)butan-2-ol in 6.5 g of methanol, and add 3■ of sodium tungstate dihydrate and concentrated hydrochloric acid. Add 0.8 g of 31% hydrogen peroxide under refluxing methanol]. 15 g was added dropwise, and the mixture was further refluxed for 2 hours. After cooling, 0.9 g of 5% aqueous sodium thiosulfate solution was added, followed by 3.1 g of 10% aqueous sodium hydroxide solution for neutralization, and methanol was distilled off under reduced pressure. 7.5 g of water and 520 μm of sodium hydroxide were added, and the mixture was kept at 60°C for 2 hours. Add i4 hydrochloric acid to pH 4
The mixture was stirred at room temperature for 1 hour, the crystals were collected by filtration, and the crystals were diluted with 2 g of water.
The sample was washed once with 2 g of cold methanol. By drying under reduced pressure, (±)1threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1,2.
4-}Riazol-l-yl)butan-2-ol 1
．． 18 g was obtained. Example 8

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, Ar is a substituted or unsubstituted phenyl group, Y is a triazole group or imidazole group, R^1 and R^
2 each represents a lower alkyl group, and n represents 0, 1 or 2. (I) Method for manufacturing the threo body.