JPS5935367B2 - Method for producing optically active alcohols - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing optically active alcohols.

More specifically, the present invention provides a ketone compound in the presence of a saccharide,
This invention relates to a method for producing optically active alcohols by reduction with a metal borohydride compound in an inert organic solvent. This production method is extremely significant from a stereochemical standpoint, and furthermore, the optically active alcohols obtained in this way can serve as intermediates for the production of useful compounds such as pharmaceuticals. BACKGROUND ART Conventionally, there has been known a method for producing optically active alcohols by subjecting ketones to asymmetric reduction using a chiral reagent.

That is, for example, a method of producing an optically active alcohol by reducing a ketone compound such as methyl ethyl ketone or propiophenone with lithium aluminum hydride and an alcohol or amine, or a method of producing an optically active alcohol by reducing a ketone compound such as methyl ethyl ketone or propiophenone, or a method of producing an optically active alcohol by reducing a ketone compound such as methyl ethyl ketone or propiophenone, or a method of producing an optically active alcohol by reducing a ketone compound such as methyl ethyl ketone or propiophenone with lithium aluminum hydride and an alcohol or amine; A method for producing an optically active alcohol under phase transfer reaction conditions using sodium, or a method for producing an optically active alcohol under phase transfer reaction conditions, or a method for producing an optically active alcohol using lithium aluminum hydride and monomers such as 3-0-benzyl-1,2-cyclohexylidene-α-D-glucofuranose. A method of producing optically active alcohol using saccharides is known.

Such a method for producing optically active alcohols has a low optical yield, and cannot be said to be a sufficiently excellent method for obtaining optically active alcohol compounds. Therefore, the present inventors have developed an excellent method with a high optical yield. In addition, as a result of intensive research to find a method for producing optically active alcohols, we found that by reducing a ketone compound in an inert organic solvent using a metal borohydride compound and a specific saccharide, we were able to achieve extremely high optical yields. The present invention was achieved by discovering that alcohols with a high alcohol content can be obtained.

That is, the present invention is directed to the following formula (1) [wherein R1 represents an alkyl group and R2 represents an allyl group with or without a substituent.

] A ketone compound represented by the following formula (
) or without an allyl group, * indicates an asymmetric carbon atom.

] This is a method for producing optically active alcohols represented by:

The ketone compound used as a raw material compound in the present invention is a ketone compound represented by the following formula (1).

In the above formula (1), R1 represents an alkyl group, and examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a pentyl group, and a hexyl group. R2 represents an allyl group with or without a substituent, and such an allyl group includes, for example, a phenyl group, a naphthyl group, or a phenyl group or a naphthyl group having a substituent such as a halogen atom, an alkyl group, or an alkoxy group. . Specific examples of such ketone compounds include acetophenone, propiophenone, propylphenyl ketone, isopropylphenyl ketone, n-butylphenyl ketone, isobutylphenyl ketone, methylnaphthyl ketone, ethylnaphthyl ketone, propyl Examples include naphthyl ketone, isopropyl naphthyl ketone, n-butyl naphthyl ketone, isobutyl naphthyl ketone, P-chloroacetophenone, -P-methylacetophenone, 0-methoxyacetophenone, p-chloropiophenone, and the like. Examples of the metal borohydride compound used to reduce such a ketone compound include sodium borohydride, potassium borohydride, lithium borohydride, and among these, sodium borohydride is particularly preferred.

Also, the formula, MBH. R4-.

Alkylated borohydride metal compounds represented by (n>1, M: alkali metal; R: alkyl group) such as sodium alkylated borohydride, lithium alkylated borohydride, etc. can also be used. The amount of such metal borohydride compound to be used is usually preferably an equimolar amount to the ketone compound represented by the above formula (1).

In the present invention, saccharides are used together with the metal borohydride compound as described above.

In the present invention, monosaccharides having 1 to 3 hydroxyl groups are used as the carbohydrates. The monosaccharides of the present invention exclude meso or racemic monosaccharides. Examples of monosaccharides having 1 to 3 hydroxyl groups used in the present invention include 2,3-isopropylidene-L-threitol, diethyl-L-tartaric acid, 1,4
:3,6-diamhitrow D sorbitol, 1,4:3
・6-dianhydro D-mannitol, 1.2:5.6-
Di-10-isopropylidene-α-D-glucofuranose, 1,2-isopropylidene-α-D-glucofuranose, 1.2:5.6-di-10-cyclohexylidene-α
-D-glucofuranose, 2.3:4.5-di-10-isopropylidene-D-fructopyranose, 1.2:4
・5-di-10-isopropylidene-D-fructopyranose, 1.2:3.4-dibenzylidene-D-sorbitol 1.2:3.4-di-10-isopropylidene-D
-galactopyranose, 1.2:5.6-diacetone-
Examples include monosaccharides having 1 to 3 hydroxyl groups such as D-manitol and diacetone-L-sorbose. Among others, 1,4:3,6-dianhythro D-sorbitol, 1,4:3,6-dianhythro D-mannitol, 1,2:5,6-di0-isopropylidene-D-glucofuranose, 1・2:5.6-di-D-cyclohexylidene D-glucofuranose, 2.3:4.5-di-0
-isopropylidene-D-fructopyranose, 1.2
:3,4-di-10-isopropylidene-D-galactopyranose and the like are preferred. The amount of sugar used is
When the saccharide has one hydroxyl group, it has twice the molar amount, when it has two hydroxyl groups, it has an equimolar amount, and when it has three hydroxyl groups, it has 2 times the molar amount of the ketone compound represented by the above formula (1). /3 times the molar amount is preferred.

When carrying out a reduction reaction in an inert organic solvent as described below using particularly sodium borohydride and a saccharide as the borohydride metal compound as in the present invention, the borohydride metal compound and the saccharide react with each other. Instead, it is thought that the ketone compound is reduced by forming a complex or by some kind of interaction.

In the present invention, by using a carboxylic acid together with a saccharide as described above, the optical yield of the obtained optically active alcohol can be further increased.

Examples of such carboxylic acids include aliphatic or aromatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, gamphoric acid, diphenylacetic acid, etc. acid,
Examples include dicarboxylic acids such as tartaric acid. In the case of carboxylic acids such as malic acid and tartaric acid in which optically active forms can exist, the optically active forms are naturally included in the above-mentioned carboxylic acids. The amount of such carboxylic acid to be used is preferably equimolar to the ketone compound represented by the above formula (), which is the raw material compound.

When the above-mentioned carboxylic acid is used together with a saccharide, it is thought that the borohydride metal compound and the carboxylic acid react first, and then the ketone compound is reduced by this reaction product and the saccharide.

This reaction formula is shown below. [In the formula, x represents the number of moles of carboxylic acid.

] Furthermore, in the present invention, by using a halogenated metal compound together with the above-mentioned saccharide, the optical yield of the obtained optically active alcohol can be increased. Examples of such metal halide compounds include aluminum chloride,
Examples include zinc chloride, magnesium chloride, barium chloride, and the like. In the case of a trivalent metal halide compound such as metal aluminum, the amount of such a metal halide compound to be used is 1/3 of that of the metal borohydride compound.
Double the molar amount, in the case of divalent substances such as zinc and magnesium,
It is preferable to use 1/2 molar amount of the metal borohydride compound. The solvent used in the reduction with sugars and/or carboxylic acids or metal halides is an inert organic solvent, such as an aliphatic solvent such as n-hexane, heptane, cyclohexane, decalin, methylcyclohexane, etc. Hydrocarbons, aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, tetrahydrofuran, dioxane, diglyme,
Preferred examples include aliphatic or aromatic ethers such as anisole, and halogenated hydrocarbons such as tetrachloroethane and perchloroethylene.

The amount of the inert organic solvent used is preferably 10 to 20 times the weight of the ketone compound represented by the above formula (1).

The reaction temperature generally ranges from -78°C to 80°C, preferably from 0°C to 40°C.

The reaction time depends on the ketone compound, sugar, carboxylic acid,
It varies depending on the heating medium, reaction temperature, etc., but usually 50 hours to 20 hours.
The range is 0 hours. When actually carrying out the reaction according to the method of the present invention, an inert organic solution in which sugars are dissolved is added to an inert organic solvent containing a metal borohydride compound, stirred for several hours, and then a ketone compound is added. can be added to allow the reaction to proceed.

In addition, when carrying out a reaction using sugars and carboxylic acids or metal halide compounds, an inert organic solution in which the carboxylic acid or metal halide compound is dissolved is added to an inert organic solvent containing a metal borohydride compound. It is also possible to proceed with the reaction by adding the inert organic solvent in which the saccharide has been dissolved, stirring for several hours, and then adding the ketone compound. The target alcohol can be isolated from the reaction mixture by methods such as vacuum distillation, recrystallization, and column chromatography.

As detailed above, in the present invention, a ketone compound is reduced in an inert organic solvent using a borohydride metal compound and a saccharide, or a saccharide and a carboxylic acid in combination, thereby achieving an extremely high optical yield. Active alcohols can be produced, and this production method is extremely significant from a stereochemical standpoint.Furthermore, the optically active alcohols obtained can be used as intermediates in the production of fine chemicals, such as pharmaceutical fragrances, and other useful compounds. It can become a body. The present invention will be explained in more detail below using Examples. Note that the present invention is not limited to these Examples. Examples 1 to 10 A solution containing a predetermined amount of monosaccharides as listed in Table 1 was added to 50ml of THF, and NaBH43OmmOl was added to THF2Om1.
The mixture was stirred at 25° C. for 3 hours.

Next, 30 mm01 of a ketone compound as listed in Table 1 was added to this THF solution, and the mixture was reacted at 25° C. for 120 hours with stirring. After the reaction, add 1NH to the resulting reaction mixture.
After adding 150ml of C and stirring for 2 hours, add 30ml of ether.
Extraction was performed three times using 1. The ether layer is 20ml of water
The mixture was washed three times with Na2sO4, and the ether was distilled off. The resulting colorless liquid was fractionated by vacuum distillation to obtain the desired alcohol. Similar experiments (Examples 3 to 9) were conducted by changing the solvent to benzene. Also NaBH4
A similar experiment (Example 10) was carried out by changing LiBH4 to LiBH4. These results are shown in Table 1. Examples 11-35 THF solutions of carboxylic acids (30 or 60 mm01/
20m1), NaBH4-THF (30mm01/1
0ml), and after the dropwise addition, the mixture was stirred at 25°C for 3 hours.

Claims (1)

[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
(I) [In the formula, R_1 represents an alkyl group and R_2 represents an allyl group with or without a substituent. ] A ketone compound represented by the following formula (
II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
...(II) [In the formula, R_1 is an alkyl group, R_2 is an allyl group with or without a substituent, and the * mark represents an asymmetric carbon atom. ] A method for producing an optically active alcohol. 2. The method for producing optically active alcohols according to claim 1, in which a carboxylic acid is used together with a monosaccharide having 1 to 3 hydroxyl groups. 3 Monosaccharides having 1 to 3 hydroxyl groups are 1.4:3.6
-dianhydro-D-sorbitol, 1.4:3.6-
Dianhydro-D-mannitol, 1.2:5.6-di-
O-isopropylidene-D-glucofuranose, 1.2
:5,6-di-O-cyclohexylidene-D-glucofuranose, 2,3:4,5-di-O-isopropylidene-D-fructopyranose and 1,2:3,4-di-
3. The method for producing optically active alcohols according to claim 1 or 2, wherein the monosaccharide is a monosaccharide selected from the group consisting of O-isopropylidene-D-galactopyranose. 4. The method for producing optically active alcohols according to claim 1, which uses a halogenated metal compound together with a monosaccharide having 1 to 3 hydroxyl groups. 5. The method for producing optically active alcohols according to claim 4, wherein the metal halide compound is a metal halide compound selected from the group consisting of aluminum chloride, zinc chloride, and barium chloride.