JPH0528227B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active azole α,β-unsaturated alcohols by asymmetric reduction of ketone compounds. More specifically, the present invention is based on the general formula () [In the formula, R ₁ is a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom, a cycloalkenyl group having 5 to 8 carbon atoms which may be substituted with a halogen atom, or a halogen atom, It represents an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a cyano group, an alkoxyl group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a phenoxy group or a phenyl group. R ₂ represents an imidazol-1-yl group or a 1,2,4-triazol-1-yl group. ] The ketone compound represented by the general formula () [In the formula, R ₃ represents an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 11 carbon atoms. R ₄ is a hydrogen atom, number of carbon atoms is 1
-6 alkyl group or C7-16 aralkyl group. R ₅ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 16 carbon atoms, or is substituted with an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms; represents an aryl group having 6 to 18 carbon atoms.
*mark means asymmetric carbon. ] The general formula () is obtained by asymmetric reduction with a borohydride reducing agent obtained by reacting the optically active amino alcohol represented by borane with 1.8 to 2.5 moles of borane. [In the formula, R ₁ , R ₂ and * represent the same meanings as above. ] This relates to a method for producing an optically active azole-based α,β-unsaturated alcohol. Azole system α, β represented by the above general formula ()
-Unsaturated alcohols are, for example, 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol, 1 -(4-chlorophenyl)-2
-(1,2,4-triazol-1-yl)-4,
4-dimethyl-1-penten-3-ol or 1-cyclohexyl-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-
As typified by penten-3-ol, it is known to be useful as an active ingredient in fungicides, plant growth regulators, or herbicides. There are significant differences in activity between optical isomers, such as the above-mentioned 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4 , 4-dimethyl-1-penten-3-ol, 1-(4-chlorophenyl)-2-(1,2,
4-triazol-1-yl)-4,4-dimethyl-
It is also known that the (-) form of 1-penten-3-ol has strong efficacy as a fungicide, and the (+) form as a plant growth regulator and herbicide (Japanese Patent Laid-Open No. 57-99575). issue and JP-A-57-
106669). For this reason, it is desired to develop a method for industrially and efficiently producing either the (-) or (+) optical isomer depending on the purpose of use. Conventionally, various reagents such as lithium aluminum hydride and sodium borohydride have been known as reducing agents for reducing the carbonyl group of ketone compounds to lead to alcohol compounds. When used, the reduction product is optically inactive or racemic, and
When the ketone compound used contains an unsaturated bond, especially when it is used to reduce an α,β-conjugated unsaturated ketone such as the raw material for the method of the present invention, in addition to the carbonyl group, the double bond site can also be reduced. This is likely to occur, and furthermore, the possibility of steric isomerization regarding the double bond also arises. Until now, as a method for asymmetric reduction of the ketone compound represented by the general formula (), for example, the general formula () [In the formula, X represents a hydrogen atom or a chlorine atom. ] The ketone compound represented by is reduced with an asymmetrically modified lithium aluminum hydride compound to form the general formula () [In the formula, X and * represent the same meanings as above. ] A method for obtaining an optically active alcohol compound represented by the following is known (JP-A-57-99575 and JP-A-57-106669). However, this method has drawbacks such as requiring a large amount of additives such as N-substituted aniline in order to obtain an alcohol compound with high optical purity. Furthermore, the following method has been reported as a method for producing optically active alcohol using an asymmetrically modified borohydride reducing agent in asymmetric reduction. S, Colona et al., J.Chem.Soc., Perkin
A method using sodium borohydride and an optically active onium salt of ephedrine as described in Trans I, 371 (1978). RF Borch et al., J.Org.Chem., 37 , 2347
(1972) using an optically active amine borane complex. MF Grundon et al., Tetrahedron Letters,
295 (1976) using a complex with α-amino acid ester borane. A.Hirao et al., J.Chem.Soc.Chem.Comm.,
315 (1981); S. Itsuno et al., ibid. 469 (1983); S.
Itsuno et al., J. Chem. Soc., Perkin Trans.
I.1673 (1983), a method for asymmetric reduction of aromatic ketones using an optically active amino alcohol and borane. However, , and have low optical yields, and both methods involve reactions in simple systems such as aromatic ketones. Under these circumstances, the present inventors have developed a method for obtaining an optically active azole-based α,β-unsaturated alcohol represented by the general formula () by asymmetric reduction of the ketone compound represented by the general formula (). As a result of extensive studies, we found that by using a borohydride reducing agent obtained by reacting an optically active amino alcohol represented by the general formula () with borane, only carbonyl groups can be selectively reduced, and moreover, carbonyl groups can be selectively reduced. It was discovered that steric isomerization related to heavy bonds was also suppressed, and the desired optically active alcohol could be obtained in high optical yield. The method of the present invention will be explained below. The optically active amino alcohol represented by the general formula () used in the method of the present invention is, for example, commercially available optically active alanine, C-phenylglycine,
Derivatives of amino acids such as phenylalanine, valine, leucine, and isoleucine have the general formula () R′ ₅ MgY () [wherein R′ ₅ is an alkyl group having 1 to 10 carbon atoms or an aralkyl group having 7 to 16 carbon atoms] , or carbon number 1~
represents an aryl group having 6 to 18 carbon atoms which may be substituted with a 6 alkyl group or an alkoxyl group having 1 to 6 carbon atoms, and Y represents a halogen atom. ] It can be produced by reacting the Grignard reagent shown in (A. Mckenzie et al., J. Chem. Soc.,
123, 79 (1928); A. Mckenzie et al., Chem. Ber.
62, 288 (1920); A. Mckenzie et al., J. Chem. Soc.
779 (1926); S. Hayashi et al., Chem. Pharm. Bull.
17, 145 (1969)). In the general formula (), R ₃ is a substituent derived from the above-mentioned amino acid derivative, specific examples of which include methyl group, isopropyl group, isobutyl group, sec-butyl group, phenyl group or benzyl group, Specific examples of R ₄ include hydrogen atom,
Examples include methyl group, ethyl group, n-propyl group or isopropyl group. Further, specific examples of R ₅ include phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 2,5-xylyl group, o-tolyl group,
methoxyphenyl group, m-methoxyphenyl group,
Examples include p-methoxyphenyl group, o-ethoxyphenyl group, benzyl group and methyl group. The reducing agent used in the present invention is in a solvent,
It is obtained by directly reacting the amino alcohol with borane. As the borane, diborane, borane-tetrahydrofuran complex, borane-dimethylsulfide complex, etc. are used. In the production of the above reducing agent, the molar ratio of borane and optically active amino alcohol is as follows in terms of boron:
Usually the ratio is 1.8:1 to 2.5:1. The solvent used is not particularly limited as long as it does not participate in the reaction, but examples include aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, methylene chloride, 1,2-dichloroethane, chloroform, and Examples include halogenated hydrocarbons such as carbon chloride, and mixed solvents thereof. The reaction temperature is usually in the range of -78 to 100°C. Note that the reaction is usually carried out in an atmosphere of an inert gas such as nitrogen or argon. Although the reducing agent thus obtained may be used after being isolated from the reaction solution, it is usually used as a solution in the next reduction reaction without being isolated. Next, using the reducing agent thus obtained, the optically active azole α,β-unsaturated alcohol represented by the general formula () is converted from the ketone compound represented by the general formula () by a reduction reaction. The manufacturing method will be described. The amount of the reducing agent used in the above-mentioned reduction reaction is 0.5 mol or more in terms of boron per 1 mol of the ketone compound, and is usually in the range of 1 to 5 mol, and 1 to 5 mol.
The purpose can be sufficiently achieved even within the range of 2 moles. Further, the solvent for the above-mentioned reduction reaction is not particularly limited as long as it is an inert solvent, but preferably,
Aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, methylene chloride, 1,2-
Organic solvents such as halogenated hydrocarbons such as dichloroethane, chloroform, and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme, or mixed solvents thereof are used, and the solvent used in the production of the reducing agent is also used. It can be used as it is or mixed with the above solvents. The reduction reaction is carried out under an inert gas atmosphere as described above. The temperature of the reduction reaction is usually in the range of -30 to 100°C, but industrially it is carried out in the range of -10 to 50°C. After carrying out the reduction reaction in this way, an aqueous solution of mineral acids such as hydrochloric acid and sulfuric acid is usually added to the reaction solution to separate it into an organic layer and an aqueous layer, and the organic layer is washed with water.
After drying, by distilling off the organic solvent, the desired optically active azole α,β-unsaturated alcohol represented by the general formula () can be easily obtained in high yield. The optical yield can be determined by measuring the degree of optical extinction of the product or by directly measuring the enantiomeric ratio by high performance liquid chromatography using an optically active packing. The optically active amino alcohol used can be easily recovered while maintaining its steric configuration by adding an alkaline aqueous solution to the aqueous layer after the reaction and extracting with an organic solvent, and can be reused. Next, the present invention will be explained in more detail with reference to Examples. Example Under a nitrogen atmosphere, (S)-2-amino-1,1-diphenyl-4-methylpentane was added to 2 ml of a borane solution in tetrahydrofuran (1.03 mmol/ml).
A solution of 274 mg (1.02 mmol) of 1-ol in 4 ml of chloroform was added dropwise at -60°C. After raising the temperature to room temperature over a period of 2 hours, (E)-1-(4-chlorophenyl)-2-(1,2,4-triazole-1-
yl)-4,4-dimethyl-1-pentene-3-
4 ml of a chloroform solution containing 168 mg (0.58 mmol) of ion was added, and the mixture was allowed to react at room temperature for 24 hours. to the reaction solution
After stirring with the addition of 1N hydrochloric acid, the organic layer was separated, concentrated, and purified by silica gel column chromatography.
54 mg of (E)-1-(4-chlorophenyl)-2-
(1,2,4-triazol-1-yl)-4,4
-dimethyl-1-penten-3-ol and 104mg
(E)-1-(4-chlorophenyl)-2-(1,
A borane complex of 2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol was obtained. Dissolve this borane complex in ether and
By stirring with hydrochloric acid for 6 hours, (E)-1-(4
-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol was obtained. All alcohols are E-form: Z-form = 96.0:4.0, and the enantiomeric ratio of E-form alcohol is (-) form: (+) form = 1.5:
It was 98.5.

Claims (1)

[Claims] 1 General formula () [In the formula, R ₁ is a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a halogen atom, a cycloalkenyl group having 5 to 8 carbon atoms which may be substituted with a halogen atom, or a halogen atom, It represents an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a cyano group, an alkoxyl group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a phenoxy group or a phenyl group. R ₂ represents an imidazol-1-yl group or a 1,2,4-triazol-1-yl group. ] The ketone compound represented by the general formula () [In the formula, R ₃ represents an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 11 carbon atoms. R ₄ is a hydrogen atom, number of carbon atoms is 1
-6 alkyl group or C7-16 aralkyl group. R ₅ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 16 carbon atoms, or is substituted with an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms; represents an aryl group having 6 to 18 carbon atoms.
*mark means asymmetric carbon. ] A general formula () characterized by asymmetric reduction with a borohydride reducing agent obtained by reacting an optically active amino alcohol represented by the formula with borane in an amount of 1.8 to 2.5 times the mole thereof. [In the formula, R ₁ , R ₂ and * represent the same meanings as above. ] A method for producing an optically active azole-based α,β-unsaturated alcohol.