JPH09241193A - Production of optically active diol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily obtain an optically active diol having high optical purity by reducing a diketone with an asymmetric reducing agent composed of a borane and a specific optically active amino alcohol having a substituted silyloxy group at 3-position. SOLUTION: The objective optically active diol of formula III is produced by reducing a diketone of formula I (R<1> to R<3> are each independently H, a lower alkyl, a lower alkoxy or a halogen) with an asymmetric reducing agent composed of an optically active amino alcohol of formula II (R<5> to R<7> are each independently H, a lower alkyl, etc., provided that R<5> to R<7> are not H at the same time; R<8> and R<9> are each II, a lower alkyl or a lower alkoxy; *represents asymmetric carbon atom) and a borane. The amount of the asymmetric reducing agent is 0.05-3mol, preferably 0.1-2mol in terms of the amino alcohol of formula II and 0.5-10mol, preferably 1-10mol in terms of baron based on the diketone of formula I.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active diol.

[0002]

BACKGROUND OF THE INVENTION Optically active diols are compounds useful as synthetic intermediates for pharmaceuticals and agricultural chemicals, or as a ligand for asymmetric synthesis. Conventionally, as a method for producing an optically active diol, for example, an optically active 1,2-
As a method for producing diphenylethane-1,2-diol, first, its racemic body is obtained by reducing the corresponding diketone, and then optically resolved by using a large amount of resolving aid (OPTICAL RESOLUTION PROCEDURES for CHEMI
CAL COMPOUNDS Vol3.P353) and optically active 2-amino-
A method for reducing benzyl with an asymmetric reducing agent obtained from 1,2-diphenylethanol and boranes (Tetrahedron Let
t. , 36, 4729 (1995).) and the like are known.

[0003]

However, the former method has a problem that it requires a complicated operation for optical resolution, and the latter method has an optical purity of 70 to 86.
It is about% ee, and there is a problem that a sufficiently high-purity target product cannot be obtained.

[0004]

Under the circumstances, the inventors of the present invention have conducted extensive studies to find a method for producing an optically active diol which does not have such a problem, and as a result, the substituted silyloxy group at the 3-position has been found. It is possible to produce optically active diols having extremely high optical purity without complicated operations by reducing the corresponding diketones with an asymmetric reducing agent obtained from specific optically active aminoalcohols and boranes having It was found that the present invention has been completed.

That is, the present invention is of the formula [I] (In the formula, R ¹ , R ² , and R ³ each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom.) (In the formula, R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom,
It represents a lower alkyl group, a phenyl group optionally substituted with lower alkyl or a benzyl group optionally substituted with lower alkyl, but not all hydrogen atoms at the same time. R ⁸ and R ⁹ represent a hydrogen atom, a lower alkyl group or a lower alkoxy group, and * represents an asymmetric carbon. ), Which is reduced by an asymmetric reducing agent obtained from an optically active amino alcohol and borane [II] (In the formula, R ¹ , R ² , R ³ and * have the same meanings as described above.) A method for producing an optically active diol is provided.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The diketones used as a raw material in the present invention are those represented by the formula [I], and the substituents R ¹ , R
² and R ³ are, for example, a hydrogen atom, methyl,
Examples thereof include lower alkyl groups such as ethyl, propyl and butyl, lower alkoxy groups such as methoxy, ethoxy, propoxy and butoxy, and halogen atoms such as chloro, bromo and fluoro. Representative compounds of diketones [I] include, for example, benzyl, 1,2-bis (3′-methylphenyl)
Ethane-1,2-dione, 1,2-bis (4'-methylphenyl) ethane-1,2-dione, 1,2-bis (3 ', 5'-dimethylphenyl) ethane-1,2-dione 1,2-bis (3'-i-propylphenyl) ethane-1,2-dione, 1,2-bis (3'-methoxyphenyl) ethane-1,2-dione, 1,2-bis (4 '-Methoxyphenyl) ethane-1,2-dione, 1,2-bis (3', 5'-dimethoxyphenyl) ethane-1,2-dione, 2-bis (3'-ethoxyphenyl) ethane-1, 2-dione, 1,2-bis (2'-methyl-
4'-methoxyphenyl) ethane-1,2-dione, 1,2-bis
(3'-chlorophenyl) ethane-1,2-dione, 1,2-bis
(2'-chlorophenyl) ethane-1,2-dione, 1,2-bis
(4'-Chlorophenyl) ethane-1,2-dione, 1,2-bis
(3 ', 5'-dichlorophenyl) ethane-1,2-dione, 1,2-
Bis (3'-bromo-5'-chlorophenyl) ethane-1,2-dione, 1,2-bis (4'-bromophenyl) ethane-1,2-dione, 1,2-bis (3'-chloro -5'-Bromophenyl) ethane-
1,2-dione, 1,2-bis (3 ', 5'-difluorophenyl)
Examples include ethane-1,2-dione.

The diketones [I] in the present invention can be obtained by a known method. For example, the corresponding benzaldehydes are condensed in the presence of potassium cyanide and then oxidized with copper acetate (Tetrahedron Asymm., 6 , 3 ( 1995).
) And the like.

The present invention is based on the above-mentioned diketones [I].
Is reduced with an asymmetric reducing agent obtained from an optically active aminoalcohol [III] and a borane. In the optically active aminoalcohol [III], the substituents R ⁵ , R ⁶ and R ⁷ is, for example, a hydrogen atom, a lower alkyl group such as methyl, ethyl, propyl or butyl, a phenyl group which may be substituted with a lower alkyl such as methyl, ethyl, propyl or butyl, methyl, ethyl, propyl, Examples thereof include a benzyl group which may be substituted with lower alkyl such as butyl, but not all of them are hydrogen atoms at the same time. Examples of the substituents R ⁸ and R ⁹ include a hydrogen atom, a lower alkyl group such as methyl, ethyl, propyl and butyl, and a lower alkoxy group such as methoxy, ethoxy, propoxy and butoxy. Representative examples of the optically active amino alcohols [III] include, for example, optically active 2-amino-3-trimethylsiloxy-1,1-diphenylbutanol and 2-amino-3- (t-butyldimethylsiloxy). ) -1,1-Diphenylbutanol, 2-amino-3- (t-butyldiethylsiloxy)-
1,1-diphenylbutanol, 2-amino-3- (t-butyldi)
-i-propylsiloxy) -1,1-diphenylbutanol,
2-Amino-3- (t-butyldiphenylsiloxy) -1,1-diphenylbutanol, 2-amino-3-trimethylsiloxy-
1,1-bis (2 ', 5'-dimethylphenyl) butanol, 2-
Amino-3- (t-butyldimethylsiloxy) -1,1-bis (2 ', 5'-dimethoxyphenyl) butanol and the like can be mentioned.

The optically active amino alcohols [III] are
It can be easily produced using optically active threonine as a starting material. For example, by reacting optically active threonine with benzyloxycarbonyl halide to protect the amino group,
Diazomethane acts to esterify carboxylic acid,
Then, t-butylsilyl halides are allowed to act to introduce a t-butylsilyl group into the hydroxy group, and then phenylmagnesium halide is allowed to act to diphenylate the ester group, followed by deprotection of the amino group to obtain good yields. The optically active amino alcohols [III] can be produced at a rate.

The present invention is characterized by using the asymmetric reducing agent obtained from the above-mentioned optically active amino alcohols [III] and boranes. Examples of the boranes are diborane and tetraborane. , Hexaborane,
Tetrahydrofuran borane complex, dimethyl sulfide borane complex, dioxane borane complex, thioxane borane complex and the like can be mentioned. The borane is usually 0.8 to 10 in terms of boron, although it depends on the amount of the optically active aminoalcohol [III] used relative to the diketone [I] which is a substance to be reduced. It is about 100 mole times, preferably about 2 to 50 mole times.

A solvent is usually used when the optically active amino alcohol [III] is reacted with borane to produce an asymmetric reducing agent. Examples of the solvent include ethers such as tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, 1,3-dioxolane, thioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and methyl-t-butyl ether, benzene, toluene, xylene. , Aromatics such as chlorobenzene, hydrocarbons such as 1,2-dimethoxyethane, hexane, heptane and cyclohexane, halogenated hydrocarbons such as methylene chloride, ethylene chloride and carbon tetrachloride,
These mixtures etc. are mentioned. The solvent is usually used in an amount of about 0.5 to 20 times by weight that of the optically active amino alcohol [III]. The reaction for producing a reducing agent is usually carried out by adding boranes to a mixture of a solvent and an optically active amino alcohol [III]. The reaction temperature is generally -20 to 100 ° C, preferably 0 to 80 ° C.

In reducing the diketone [I] using the thus obtained asymmetric reducing agent, the asymmetric reducing agent can be isolated and used, but it is usually used as it is. The asymmetric reducing agent is usually used in an amount of about 0.05 to 3 mol, preferably about 0.1 to 2 mol, in terms of the optically active amino alcohol [III], based on the diketone [I]. It is usually about 0.5 to 10 mol, preferably about 1 to 10 mol in terms of boron.

The reduction reaction can also be carried out in the presence of a Lewis acid. The Lewis acid is not particularly limited, for example, aluminum compounds such as aluminum chloride, aluminum bromide, triphenoxyaluminum, triisopropoxyaluminum, methyldiphenoxyaluminum, zinc compounds such as zinc chloride and zinc bromide, titanium chloride. Examples thereof include titanium compounds such as titanium bromide, boron compounds such as boron chloride, boron bromide and boron fluoride, and silicon compounds such as trimethylsilyl chloride and t-butyldimethylsilyl chloride. Such Lewis acid is usually used in an amount of 0.3 to 0.3 with respect to the diketone [I].
About 5 mol, preferably about 0.5 to 3 mol can be used.

As a specific method of the reduction reaction, for example, a method of adding a diketone [I] or a mixture of this and a solvent to a mixture of an asymmetric reducing agent and a solvent, a diketone [I]
Alternatively, a method of adding an asymmetric reducing agent or a mixture of this and a solvent to a mixture of this and a solvent, or a mixture of an optically active amino alcohol [III] and a solvent, a diketone [I] or a mixture of this and a solvent Examples thereof include a method of simultaneously adding the mixture and boranes. All of these can be carried out in the presence of a Lewis acid. As a preferred method, a diketone [I] or a mixture of the same and a solvent, and borane are simultaneously added to a mixture of an optically active amino alcohol [III] and a solvent, and an optically active amino alcohol [III]. A method in which a Lewis acid is added to a mixture of a solvent and a solvent, and then a diketone [I] or a mixture of the diketone [I] or the solvent and a borane are added at the same time. Examples of the solvent used in the reduction reaction include the same solvents as those shown in the manufacturing process of the asymmetric reducing agent. When a solvent is used, its amount is usually about 0.5 to 30 times by weight that of the diketone [I]. The temperature of the reduction reaction is usually -20 to 100 ° C, preferably 0 to 80 ° C.

Thus, an optically active diol [II] is produced. For isolation of this, for example, a mineral acid such as hydrochloric acid or an aqueous solution such as a phosphate buffer is added to the reaction mass to decompose the reducing agent. After that, a poorly soluble organic solvent is added to water to extract a crude product, and then the solvent is distilled off from the separated organic phase, whereby the crude product can be easily isolated. The isolated optically active diol [II] can be further purified by subjecting it to purification means such as recrystallization and various chromatography. In addition, the optically active amino alcohols [II
I] is an optically active diol [II] obtained by the above method or the like.
Can be separated from the reaction mass after isolation, recovered, and reused. The optically active diol [II] obtained in the present invention is a diketone [I] used as a starting material.
And a representative compound is, for example,
1,2-diphenylethane-1,2-diol, 1,2-bis (3'-methylphenyl) ethane-1,2-diol, 1,2-bis (4'-methylphenyl) ethane-1,2 -Diol, 1,2-bis (3 ', 5'
-Dimethylphenyl) ethane-1,2-diol, 1,2-bis
(3'-i-propylphenyl) ethane-1,2-diol, 1,2-
Bis (3'-methoxyphenyl) ethane-1,2-diol, 1,
2-bis (4'-methoxyphenyl) ethane-1,2-diol,
1,2-bis (3 ', 5'-dimethoxyphenyl) ethane-1,2-diol, 2-bis (3'-ethoxyphenyl) ethane-1,2-diol, 1,2-bis (2'- Methyl-4'-methoxyphenyl) ethane-1,2-diol, 1,2-bis (3'-chlorophenyl) ethane-1,2-diol, 1,2-bis (2'-chlorophenyl) ethane-1, 2-diol, 1,2-bis (4'-chlorophenyl) ethane-1,2-diol, 1,2-bis (3 ', 5'-dichlorophenyl) ethane-1,2-diol, 1,2-bis (3'-Bromo-5'-chlorophenyl) ethane-1,2-diol, 1,2-bis (4'-bromophenyl) ethane-1,2-diol, 1,2-bis (3'-chloro- 5'-Bromophenyl) ethane-1,2-diol, 1,2-
An optically active substance such as bis (3 ′, 5′-difluorophenyl) ethane-1,2-diol may be mentioned.

[0016]

According to the present invention, the diketone [I] is reduced by reducing the diketone [I] with an asymmetric reducing agent obtained from an optically active amino alcohol [III] having a substituted silyloxy group at the 3-position and borane. An optically active diol [II] having extremely high purity can be produced without complicated operations.

[0017]

The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited to these examples.

Example 1 (2S, 3R) -2-in a 30 ml flask at room temperature under an argon atmosphere.
Amino-3- (t-butyldimethylsiloxy) -1,1-diphenylbutanol 22.3 mg (0.06 mmol) in 1,2-dimethoxyethane solution 0.3 ml was added, and the tetrahydrofuran borane complex was added here.
1.5 mmol of tetrahydrofuran solution (1.5 ml) and benzyl 6
1.5 ml of a 1,2-dimethoxyethane solution of 3.1 mg (0.3 mmol) was simultaneously added dropwise over 3 hours, the mixture was stirred for 6 hours, and then 20 ml of 2N hydrochloric acid was added. It was then extracted with 100 ml of ethyl acetate. The obtained extraction layer is dried over anhydrous sodium sulfate,
Concentration under reduced pressure gave an oil. This was purified by thin-layer chromatography (eluting solvent hexane / ethyl acetate = 2/1) to give 1,2-diphenylethanediol 63.9
mg was obtained. [Α] ²³ _D −33 ° (c 1.3, ethanol) ¹ H-NMR (270MHz, CDCl ₃ ) δ 2.29 (br, 2H), 4.66 (s, 2H), 4.79 (s, 2H), 7.07-7.29
When analyzed by high performance liquid chromatography using an (m, 10H) optically active column, the diastereomer ratio was dl body / meso body = 50.
The optical purity of the / 50, (1S, 2S) body was 99% ee or higher.

Example 2 (2S, 3R) -2- in a 30 ml flask at room temperature under an argon atmosphere.
Amino-3- (t-butyldimethylsiloxy) -1,1-diphenylbutanol 111.5 mg (0.3 mmol) in 1,2-dimethoxyethane solution 0.3 ml to triisopropoxyaluminum 61.5 mg (0.3
mmol), and then tetrahydrofuran borane complex 1.5 m
1.5 ml of tetrahydrofuran solution in mol and benzyl 63.7 mg
Simultaneously with 1.5 ml of a solution of (0.3 mmol) in 1,2-dimethoxyethane
Add dropwise over 3 hours, stir for 16 hours, then add 2N hydrochloric acid.
20 ml was added. Then, 50 mg of 1,2-diphenylethanediol was obtained by treating and purifying according to Example 1. Diastereomeric ratio is dl body / meso body = 51/49, (1S, 2S)
The optical purity of the body was 98% ee.

Example 3 In Example 2, 86.6 μl of trimethylsilyl chloride was used instead of the prepared triisopropoxyaluminum.
(0.68mol), the amount of each compound used (2S, 3R) -2-amino-3- (t-butyldimethylsiloxy) -1,1-diphenylbutanol 126.6mg (0.34mmol) 1,2- Dimethoxyethane solution
0.34ml, tetrahydrofuran borane complex 1.7mmol tetrahydrofuran solution 1.7ml, benzyl 72.5mg (0.34mmol)
Was replaced with 1.7 ml of the 1,2-dimethoxyethane solution of No. 1, except that the dropping time of the tetrahydrofuran solution of the tetrahydrofuran borane complex and the benzyl 1,2-dimethoxyethane solution was changed to 3.5 hours. 53 mg of 1,2-diphenylethanediol was obtained. Diastereomer ratio is dl body / meso body = 50/50, optical purity of (1S, 2S) body is 95% ee
Met.

Example 4 In Example 2, a solution of benzyl in 1,2-dimethoxyethane was added to 1,2-bis (3 ', 5'-dimethylphenyl) ethanedione 4
3.5 mg (0.16 mmol) of 1,2-dimethoxyethane solution in place of 0.8 ml, (2S, 3R) -2-amino-3- (t-butyldimethylsiloxy) -1,1-diphenylbutanol 1,2- Use the amount of dimethoxyethane solution (2S, 3R) -2-amino-3- (t-butyldimethylsiloxy) -1,1-diphenylbutanol 43.5 mg (0.16 mmol)
Was carried out according to Example 2, except that 0.8 ml of the 1,2-dimethoxyethane solution prepared in Example 1 was replaced with 0.8 ml of the tetrahydrofuran solution containing 0.8 mmol of the tetrahydrofuran borane complex. 26 mg of 2-bis (3 ', 5'-dimethyldiphenyl) ethanediol was obtained. [Α] ²³ _D −39 ° (c 0.94, ethanol) ¹ H-NMR (270MHz, CDCl ₃ ) δ 2.71 (br, 2H), 2.25 (s, 2H), 2.31 (s, 2H), 4.59 (s, 2
H), 4.62 (s, 2H), 6.74-6.96 (m, 2H) diastereomer ratio was dl body / meso body = 53/47, and the optical purity of (1S, 2S) body was 98% ee.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 41/26 7419-4H C07C 41/26 43/23 7419-4H 43/23 A // C07M 7 : 00

Claims (2)

[Claims] 1. The formula [I] (In the formula, R ¹ , R ² , and R ³ each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom.) (In the formula, R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom,
It represents a lower alkyl group, a phenyl group optionally substituted with lower alkyl or a benzyl group optionally substituted with lower alkyl, but not all hydrogen atoms at the same time. R ⁸ and R ⁹ represent a hydrogen atom, a lower alkyl group or a lower alkoxy group, and * represents an asymmetric carbon. ), Which is reduced by an asymmetric reducing agent obtained from an optically active amino alcohol and borane [II] (In the formula, R ¹ , R ² , R ³ and * have the same meanings as described above.) A method for producing an optically active diol. 2. A diketone and a borane are simultaneously added to the optically active amino alcohol.
The method for producing an optically active diol according to the item 1.