JPH0528230B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for asymmetric reduction of ketone compounds. For more details, please refer to 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 or a cycloalkyl group having 5 to 8 carbon atoms which may be substituted with a halogen atom
represents a cycloalkenyl group. R ₂ represents an imidazol-1-yl group or a 1,2,4-triazol-1-yl group. R ₃ represents a t-butyl group or a 1,1-dimethyl-2-phenylethyl group in which the benzene ring may be substituted with a halogen atom. ] The ketone compound represented by the general formula () [In the formula, R ₄ represents an aryl group, an alkyl group, a cycloalkyl group, or an aralkyl group. _R5
represents an aryl group, an alkyl group, an aralkyl group or an alkoxycarbonyl group. R ₆ represents a hydrogen atom, an alkyl group or an aralkyl group. *
means an asymmetric carbon. ] Asymmetric reduction in the presence or absence of acids with an asymmetrically modified borohydride compound obtained by reacting an optically active amino alcohol or a salt thereof with an acid represented by a borohydride compound. Featured general formula () [In the formula, R ₁ , R ₂ , R ₃ and * have the same meanings as above. ] The present invention relates to a method for producing an optically active alcohol derivative shown in the following. Alcohol derivatives represented by the above general formula (), i.e. azole α,β-unsaturated alcohol derivatives, such as 1-cyclohexyl-2-(1,2,
It is known to be useful as an active ingredient of fungicides or plant growth regulators, such as 4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol ( Japanese Unexamined Patent Publication 1973-
111477), and in its activity, there is a remarkable difference between the optical isomers, as shown in the reference test example below, and the (-)-(E) isomer has its (+)-
It has an excellent plant growth regulating effect compared to the racemic body, racemic body, or Z-type racemic body. 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. As a method for producing optically active alcohol derivatives by asymmetric reduction, there is a method in which a ketone compound is asymmetrically reduced with lithium aluminum hydride modified with an optically active compound. Method using methylefedrin (I. Jacquet et al., Tetra-hedron
Letters, 1974, 2065; JPVigneron et al.
Tetrahedron, 32, 939 (1976); JPVigneron et al.
Tetrahedron Letters, 1979, 2683; idem,
ibid., 1980, 1735; JP-A No. 57-99575; JP-A-Sho
57-106669), a method using optically active proline derivatives (M. Asami et al., Heterocycles, 12, 499
(1979) or a method using optically active binaphthyl derivatives (R. Noyori et al., J. Am. Chem. Soc., 101,
3129 (1979); R. Noyori et al., Ibid., 101, 5843
(1979)). However, these methods involve the risk of ignition due to contact with moisture due to the use of (1) lithium aluminum hydride, and (2)
In order to obtain an alcohol compound with higher optical purity, this method is not necessarily industrially sufficient because it requires a large amount of additives such as N-substituted aniline. 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 Trans.
A method using sodium borohydride and an optically active onium salt of ephedrin as described in I, 371 (1978). RFBorch et al., J.Org.Chem., 37, 2347
(1972) using an optically active amine borane complex. MFGrundon et al., Tetrahedron Letters,
295 (1976) using an α-amino acid ester borane complex. A.Hirao et al., J.Chem.Soc.Chem.Comm.,
315 (1981); S. Itsuno et al., ibid., 469 (1988); 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 cannot be called a practical method. Another drawback is that in order to achieve a high optical yield, twice as much borane as the amino alcohol is used in terms of boron, which is not necessarily sufficient for industrial implementation. Under these circumstances, the present inventors have conducted intensive studies on a method for obtaining an optically active alcohol derivative represented by the general formula () by asymmetric reduction of the ketone compound represented by the general formula (). By using an asymmetrically modified borohydride compound obtained by reacting an optically active amino alcohol represented by the general formula () or a salt thereof with an acid with a borohydride compound, only the carbonyl group can be selectively removed. It has been found that the desired optically active alcohol derivative can be obtained safely and efficiently through reduction. The present invention will be explained below. In the optically active amino alcohol represented by the general formula () in the present invention, specific examples of the substituent R ₄ include an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 5 to 10 carbon atoms, and a cycloalkyl group having 7 to 16 carbon atoms. an aralkyl group, or a phenyl group optionally substituted with a halogen atom, an alkyl group, a cyano group, an alkoxyl group, or an alkoxycarbonyl group, or a phenyl group optionally substituted with a halogen atom, an alkyl group, a cyano group, an alkoxyl group, or an alkoxycarbonyl group. Specific examples of _R5 include aryl groups having 6 to 16 carbon atoms, alkyl groups having 1 to 10 carbon atoms, and naphthyl groups having 7 to 10 carbon atoms.
16 aralkyl groups, the number of carbon atoms in the alkyl moiety is 1 to
10, and specific examples of R ₆ include hydrogen atom, carbon number 1 to
Examples include an alkyl group having 6 carbon atoms or an aralkyl group having 7 to 16 carbon atoms. More specifically, the general formula ()
Examples of optically active amino alcohols include optically active norefuedrin, norpseudoefedrin, threonine ester, 1,2-diphenyl-2-amino-1-ethanol, 1-(2,5
-dimethylphenyl)-2-amino-1-propanol, 1-(2,5-dimethoxyphenyl)-2
-Amino-1-propanol, 1-(2,5-dimethoxyphenyl)-2-amino-1-propanol, 1-(2,4-dimethoxyphenyl)-2-
Amino-1-propanol, 1-(2,5-dipropoxyphenyl)-2-amino-1-propanol, 1-(2-methoxy-5-methylphenyl)
-2-amino-1-propanol, 1-(4-methoxy-2-methylphenyl)-2-amino-1
-propanol, 1-(2,4-dimethylphenyl)-2-amino-1-propanol, 1-(2,
4,6-trimethylphenyl)-2-amino-1
-propanol or 1-α-naphthyl-2-amino-1-propanol.
These are, for example, MJ Kalm, J.Org.Chem., 25,
1929-37 (1960); WH Hartung et al., J.Am.Chem.
Soc.52, 3317-22 (1930); WHHartung et al., J.
Am.Chem.Soc.51, 2262-6 (1929); MC
It is produced by the method described in Kloetzel et al., J.Org.Chem.11, 390-4 (1946). In the present invention, a halogen atom represents a fluorine atom, a chlorine atom, or a bromine atom. When the asymmetrically modified borohydride compound used in the present invention is a metal borohydride, the borohydride compound is prepared by combining a salt of an optically active amino alcohol represented by the general formula () with an acid and a borohydride compound in a solvent. It can be obtained by reacting metals, and when the borohydride compound is borane, it can be obtained by directly reacting an optically active amino alcohol represented by the general formula () with borane in a solvent. Examples of acids that are raw materials for the above-mentioned salts of optically active amino alcohols include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, carboxylic acids such as acetic acid, and organic sulfonic acids such as p-toluenesulfonic acid. It will be done. Also, whether the salt is used as the salt itself, or
During production, it may be generated in advance from an optically active amino alcohol and an acid in the system. Examples of the above-mentioned metal borohydride include sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, etc., but the present invention can be achieved by using sodium borohydride, which is usually easily available. can fully achieve the purpose of Examples of borane include diborane, borane-tetrahydrofuran complex, and borane-sulfide complex. The molar ratio of the borohydride compound and the optically active amino alcohol is 0.7:1 to 2:1 in terms of boron when the borohydride compound is metal borohydride;
Preferably 0.7:1 to 1.3:1, more preferably 1:1, and in the case of borane, 0.7:1 to
The ratio is 1.3 to 1, preferably 1:1. 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-dichloromethane, chloroform, and tetrachloride. A halogenated hydrocarbon such as carbon or a mixed solvent thereof.
Further, when metal borohydride is used, dimethyl sulfoxide, diglyme, dimethyl formamide, 1,3-dimethyl-2-imidazolidinone, etc. can also be used together in order to dissolve the metal borohydride. Also, the reaction temperature is usually -78
-100°C, preferably -40 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. The amount of the reducing agent used in the reduction reaction of the ketone compound represented by the general formula () to the optically active alcohol derivative represented by the general formula () using the reducing agent thus obtained is as shown in the general formula (). The amount is 0.5 mol or more in terms of boron per 1 mol of the ketone compound shown, usually in the range of 1 to 5 mol, and even in the range of 1 to 2 mol, the purpose can be sufficiently achieved. 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, 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 of two or more of these are used, and in the production of the reducing agent. The solvent used can be used as it is or in combination with the above solvents. The reduction reaction is usually 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. In addition, in the above-mentioned reduction reaction, the reaction can also be carried out in the presence of acids. In particular, when sodium borohydride is used as a raw material for the reducing agent, the E-form and Z-form of the ketone compound represented by the general formula () Isomerization between bodies is suppressed, and the yield of the desired optically active alcohol derivative can be increased. Examples of the above-mentioned acids include Lewis acids such as titanium tetrachloride, boron trifluoride etherate, and aluminum chloride; carboxylic acids such as acetic acid, chloroacetic acid, and propionic acid; and mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid. The molar ratio of such acids to ketone compounds is usually in the range of 0.01:1 to 1:1, preferably in the range of 0.01:1 to 0.5:1. After carrying out the reduction reaction in this way, an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid is usually added to the reaction solution to separate the organic layer and the aqueous layer, and the organic layer is washed with water and dried. By distilling off the solvent, the desired optically active alcohol derivative represented by the general formula () can be easily obtained in high yield. The optical yield is 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 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 detail with reference to Examples.
The present invention is not limited to these. Example 1 (-)-Norehuedrine hydrochloride under nitrogen atmosphere
0.507 g (2.7 mmol) was suspended in 7.5 ml of 1,2-dichloroethane, cooled to -30°C, and a solution of 0.1021 g (2.7 mmol) of sodium borohydride in 1.5 ml of dimethylformamide was added, and the mixture was heated from -30°C for 2 hours. It was kept at room temperature. Next, (E)-1-cyclohexyl-4,4-dimethyl-
2-(1,2,4-triazol-1-yl)-1
-Penten-3-one (E/Z=99.9/0.1) 0.47
g (1.8 mmol) of 1,2-dichloroethane 6
ml solution was added at room temperature and stirred for 24 hours. Then 2N
It was decomposed by adding 6 ml of hydrochloric acid. The organic layer was washed with water and concentrated under reduced pressure, and the residue was purified by column chromatography using 8 g of silica gel in chloroform solvent and concentrated under reduced pressure to obtain (-)-(E)-1-cyclohexyl-4,4-dimethyl-2. -(1, 2,
4-triazol-1-yl)-1-pentene-
0.47 g of crude crystals of 3-ol were obtained, and analysis by gas chromatography showed that the reaction rate was 99.5%. The composition of the product was 94.9% E-form alcohol and 5.1% Z-form alcohol. The enantiomeric ratio of E-form alcohol is (-)- form 79.7%, (+)- form
It was 20.3%. Examples 2 to 4 In Example 1, (−)-1-α-naphthyl-2-amino-1-propanol hydrochloride, (+)-1-(2,
Example 1 except that 5-dimethylphenyl)-2-amino-1-propanol hydrochloride or (+)-1-(2,5-dimethoxyphenyl)-2-amino-1-propanol hydrochloride was used. It was carried out in accordance with. The results are shown in Table-1.

[Table] Example 5 In Example 1, instead of (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one (Z)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazole-1-
)-1-penten-3-one (E/Z=0.1/
99.9) was carried out according to Example 1, except that
(-)-(Z)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol was obtained. The reaction rate is 100%, and the product composition is Z alcohol
98.0%, E-form alcohol 2.0%, and the specific light extinction was [α]D-10.8° (c=1.0, CHCl ₃ ). Example 6 The same procedure as in Example 5 was carried out except that (+)-norefuedrine hydrochloride was used in place of (-)-norefuedrine hydrochloride, and (+)-
(Z)-1-cyclohexyl-4,4-dimethyl-
2-(1,2,4-triazol-1-yl)-1
-Penten-3-ol was obtained. The reaction rate is 100%
The product is 99.9% Z-form alcohol and 1.0% E-form alcohol, and the specific light intensity is [α]D+
It was 10.1° (c=1.0, CHCl ₃ ). Example 7 Under nitrogen atmosphere (-)-norehuedrine hydrochloride
0.338 g (1.8 mmol) was suspended in 5 ml of 1,2-dichloroethane to which 15.4 μl (0.27 mmol) of acetic acid had been added, cooled to -30°C, and dissolved in sodium borohydride.
A 1 ml solution of 0.0749 g (1.98 mmol) in dimethylformamide was added and the mixture was warmed to room temperature from -30°C over 2 hours. Next, this suspension was added to (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-
triazol-1-yl)-1-penten-3-
On (E/Z=99.9/0.1) 0.31g (1.2 mmol)
A solution of 10.3 μl (0.18 mmol) of acetic acid in 1,2-dichloroethane was added at room temperature and stirred for 24 hours. The following procedure was carried out according to Example 1, and (-)-(E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,
4-triazol-1-yl)-1-pentene-
3-ol was obtained. The reaction rate was 100%, and the composition of the product was 97.4% E-form alcohol and 2.6% Z-form alcohol, and the enantiomeric ratio of E-form alcohol was 77.7% (-)-form and 22.3% (+)-form. It was hot. Reference test example Rice growth suppression effect Rice (variety: Nipponbare) seeds were immersed in a dark place at 30℃ for 2 days for germination treatment, then uniform seeds were selected and a vial containing 2ml of a test solution of a specified concentration (diameter 27mm x height 110mm)
8 grains were sown in each medium (mm). After cultivation for 10 days at 30°C under continuous lighting conditions of 12,000 lux, the above-ground plant height was measured. The results are shown in Table 2.

【table】

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 or a cycloalkyl group having 5 to 8 carbon atoms which may be substituted with a halogen atom
represents a cycloalkenyl group. R ₂ represents an imidazol-1-yl group or a 1,2,4-triazol-1-yl group. R ₃ represents a t-butyl group or a 1,1-dimethyl-2-phenylethyl group in which the benzene ring may be substituted with a halogen atom. ] The ketone compound represented by the general formula [In the formula, R ₄ represents an aryl group, an alkyl group, a cycloalkyl group, or an aralkyl group. _R5
represents an aryl group, an alkyl group, an aralkyl group or an alkoxycarbonyl group. R ₆ represents a hydrogen atom, an alkyl group or an aralkyl group. *
means an asymmetric carbon. ] Asymmetric reduction in the presence or absence of acids with an asymmetrically modified borohydride compound obtained by reacting an optically active amino alcohol or a salt thereof with an acid represented by a borohydride compound. Featured general formula [In the formula, R ₁ , R ₂ , R ₃ and * have the same meanings as above. ] A method for producing an optically active alcohol derivative.