JPS60248675A - Preparation of optically active azole-type alpha,beta-unsaturated alcohol - Google Patents

Abstract

PURPOSE:To suppress the isomerization of the steric configuration and to improve the optical yield in the asymmetric reduction of a ketone compound to produce the titled compound useful as a fungicide, etc., by carrying out the selective reduction of the ketone compound with a reducing agent prepared by the reaction of a specific optically active amino-alcohol with a borane. CONSTITUTION:The compound of formula III is prepared by reducing the ketone compound of formula I (R1 is 3-8C cycloalkyl, 5-8C cycloalkenyl, or phenyl; R2 is imidazol-1-yl or 1,2,4-triazol-1-yl) with a borohydride reducing agent obtained by the reaction of 1mol of an optically active amino-alcohol of formula II (R3 is 1-8C alkyl, 6-10C aryl, or 7-11C aralkyl; R4 is H, 1-6C alkyl or 7-16C aralkyl; R5 is H, 1-10C alkyl, 7-16C aralkyl, etc.; * represents asymmetric carbon atom) with 1.8-2.5mol of borane. The amount of the reducing agent is preferably 1-5mol (in terms of boron) based on 1mol of the ketone compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active azole-based a,β-unsaturated alcohols by asymmetric reduction of ketone compounds. More specifically, the present invention is based on the general formula % (%) where Rx is a cycloalkyl group having 8 to 8 carbon atoms which may be substituted with a halogen atom, or a cycloalkyl group having 5 to 8 carbon atoms which may be substituted with a halogen atom. 8 cycloalkenyl group, or a halogen atom, 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 phenoxy group, or a phenyl group. represents an optional phenyl group. R2 represents an imitazol-1-yl group or a 1,2.4-triazol-1-yl group. ] A ketone compound represented by the general formula (I[) [wherein, R3 is an alkyl group having 1 to 8 carbon atoms,
It represents a 10 aryl group or an aralkyl group having 7 to 11 carbon atoms. R4 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group having 7 to 16 carbon atoms. R
5 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or an aralkyl group having 7 to 16 carbon atoms, or 5 is substituted with an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms. represents an optionally carbon 6-18 aryl group. The tether sign means asymmetric carbon. ] Optically active amino alcohol shown by and 1 for it
．． We decided to carry out asymmetric reduction using a borohydride reducing agent obtained by reacting 8 to 2.5 moles of poran. L general formula (
TII) [In the formula, R1, B.2 and the connecting mark have the same meanings as above. ] This relates to a method for producing an optically active azole α, β-unsaturated alcohol represented by the following: Azole α represented by the above general formula (■1).

The β-unsaturated alcohol is, for example, 1-(2,4-dichlorophenyl)-2-(1,2,4-triazole-1-
yl)-4,4-dimethyl-1-penten-3-ol, ■-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-pentene -3-ol or 1-cyclohexyl-2-(
As represented by 1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-8-ol,
Bactericides and plant growth regulators are known to be useful as active ingredients in 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-8-ol, 1-(4-chlorophenyl)-2-(1,2°4-triazol-1-yl)-4
, 4-dimethyl-1-penten-3-ol is known to have strong efficacy as a fungicide (←) and as a plant growth regulator and herbicide (+). No. 57-99575 Omabi JP-A-57-10
Publication No. 6669).

For this reason, there is a desire to develop a method for industrially (and efficiently) producing either the (0-isomer or +)-isomer depending on the purpose of use.

Conventionally, various reagents such as lithium aluminum hydride and sodium borohydride have been known as reducing agents that reduce the carbonyl group of ketone compounds and lead to alcohol compounds. In this case, the reduction product is optically inactive, ie racemic, and if the ketone compound used contains an unsaturated bond, especially α, β −
When used to reduce conjugated unsaturated ketones, reduction of double bond sites in addition to carbonyl groups is likely to occur, and furthermore,
The possibility of steric isomerization regarding the double bond also arises.

Up to now, methods for asymmetric reduction of the ketone compound represented by the general formula (I) have been carried out using, for example, the general formula () [wherein X represents a hydrogen atom or a chlorine atom]. ] The ketone compound represented by these is reduced with an asymmetrically modified lithium aluminum hydride compound to form a compound of the general formula (V) [wherein X and the arrow represent the same meanings as above. ] A method for obtaining an optically active alcohol compound represented by
-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 an optically active alcohol using an asymmetrically modified borohydride reducing agent in asymmetric reduction.

■ 8. Colona et al., J. Chem, 8oc.
Perkin Trans■, 371 (1978)
A method using sodium borohydride and an optically active onium salt of ephedrine as described in .

■ R, F, Borch et al., J, Org, Ch.
A method using an optically active amine borane complex described in Em., 87 +2347 (1972).

■ M, F., Grundon et al., Tetrahe
Dron Letters.

295 (1976) using the a-amino acid ester holane complex.

■ A, Hirao et al., J. Chem, 8oc.
Chem, Corwn.

815 (198] ) i 8. Itsuno et al.
1 bid.

469 (198B); 8. Itsuno et al.
Chem.

Soc, Perkin Trans I, 167
A method for asymmetric reduction of an aromatic ketone using an optically active amino alcohol and borane described in B (198B).

However, (1), (2) and (2) have low optical yields, and all of these methods involve reactions in simple systems such as aromatic ketones.

Under these circumstances, the present inventors developed the general formula (D
The ketone compound represented by is asymmetrically reduced to form the general formula (III
) is the optically active azole system σ.

As a result of extensive research into methods for obtaining β-unsaturated alcohols, we found that by using a borohydride reducing agent obtained by reacting an optically active amino alcohol represented by the general formula (Il) with borane, carbonyl groups can be obtained. We have found that the desired optically active alcohol F'4 can be selectively reduced, and the isomerization of the configuration regarding the double bond is also suppressed, so that the desired optically active alcohol F'4 can be obtained in a high optical yield1. I will explain about it.

The optically active amino alcohol represented by the general formula (Il,) used in the method of the present invention is generally a commercially available optically active amino acid derivative such as alanine, C-phenylglycine, phenylalanine, valine, leucine, isoleucine, etc. Formula (VI) R5MgY CVJ') [In the formula, R5 is an alkyl group having 1 to 10 carbon atoms, 7 carbon atoms
~■ represents a 6 aralkyl group, or an aryl group having 6 to 18 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms;
represents a halogen atom. ] or by reducing the above-mentioned amino acid derivatives (AoMckenZie, J., Chem.

Soc,, 128, 79 (192B) i A
, Mckenzie et al., Chem. Ber, 62
, 288 (1920) iA, McKenzie
et al., J. Chem, 8oc, '179C192
6) iS, Hayashi et al., Chem, Ph
arm, Bull,, l 7.

145 (1969)).

In the general formula (Shun), R3 is a substituent derived from the above-mentioned amino acid derivative, and specific examples thereof include a methyl group,
Examples include isopropyl group, isobutyl group, 5ec-butyl group, phenyl group or benzyl group, and specific examples of R4 include hydrogen atom, methyl group, ethyl group, n-propyl group or isopropyl group. Can be mentioned. Also R5
Specific examples include phenyl group, 0-tolyl group, m-tolyl group, P-tolyl group, 2.5-xylyl group, 0-
Examples include methoxyphenyl group, m-methoxyphenyl group, p-methoxyphenyl group, o-ethoxyphenyl group, benzyl group and methyl group.

The reducing agent used in the present invention is obtained by directly reacting the amino alcohol with borane in a solvent. 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 usually 1.8:1 in terms of boron.
The solvent used is not particularly limited as long as it does not participate in the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, etc. Methylene chloride, 1,2-zig0
Examples include halogenated hydrocarbons such as ethane, chloroform, and carbon tetrachloride, 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 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 ketone compound represented by the general formula (I) is converted to the ketone compound represented by the general formula (I).
A method for producing an optically active azole α/β-unsaturated alcohol represented by lI[) by a reduction reaction 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,
The amount is usually in the range of 1 to 5 moles, and even in the range of 1 to 2 moles, the purpose can be sufficiently achieved.

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. Organic solvents such as halogenated hydrocarbons such as 2-dichloroethane, chloroporum, and carbon tetrachloride, and ethers such as diethyl etheropenatetrahydrofuran, dioxane, and diglyme are used. The solvent used in the production of the agent can be used as it is or mixed with the above solvent. The reduction reaction is carried out under an inert gas atmosphere as described above. The temperature of the reduction reaction is usually -30 to 10
Although the temperature is in the range of 0°C, industrially it is carried out in the range of -10 to 50'C. After performing 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. is added, separated into an organic layer and an aqueous layer, the organic layer is washed with water and dried, and then the organic solvent is distilled off to easily obtain the target general formula (I
The optically active azole a, β-unsaturated alcohol represented by [l] can be obtained in high yield.

The optical yield can be determined by measuring the optical rotation 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 in one piece while retaining its steric configuration by adding an alkaline aqueous solution to the aqueous layer after the above reaction and extracting with an organic solvent.
Can be reused.

Next, the present invention will be explained in more detail with reference to actual examples.

Practical Example Under a nitrogen atmosphere, a small amount of tetrahydrofuran solution (1,
A chloroform solution of 274 mg (1,02 mmol) of <8,)-2-amino-1,1-diphenyl-4-methylpentan-1-ol (4-) was added dropwise to (11 mmol/-) at -60°C. It took 1.2 hours to warm up to room temperature -4,4-dimethyl-1-penten-3-one 1
A solution of 68 mg (0.58 mmol) in chloroform 4-
was added and allowed to react at room temperature for 24 hours. After adding IN hydrochloric acid to the reaction solution and stirring, the layers were separated, and the organic layer was concentrated and purified by silica gel column chromatography to obtain (E)-1 from 54.
-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol and (E)-1-(4-chlorophenyl) )-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol borane complex was obtained. Dissolve this borane complex in ether and
)(E)-1-(4) by stirring with N-hydrochloric acid for 6 hours.
-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-
Oars were obtained. Both alcohols are E-form = Z-form =
The enantiomeric ratio of the E-form alcohol was 96.0:4.0, and the enantiomeric ratio of the (-)-form alcohol was 1.5:98.5.

Claims (1)

[Claims] General formula (I) CHa 11 [In the formula, R1 is a 5-8 cycloalkenyl group substituted with a halogen atom;
-4 alkyl group, a haloalkyl group having 1 to 4 carbon atoms, a cyano group, an alkoxyl group having 1 to 4 carbon atoms, a phenoxy group (optionally substituted with azuryl or phenyl group).几2 is imidazole-1t represents an aralkyl group having 7 to 16 carbon atoms;
It represents an aryl group having 6 to 18 carbon atoms which may be substituted with 1 to 6 alkyl groups or an alkoxyl group having 1 to 6 carbon atoms. Old seal means asymmetric carbon. ] 7 The optically active amino alcohol shown and 1 and 1
．． 8 to 2.5 moles of phorane is reacted and asymmetric reduction is carried out with a borohydride reducing agent to form OHCH3 [wherein R1, R2 and arrows have the same meanings as above. ] A method for producing an optically active azole-based a, β-unsaturated alcohol.