JPH0582371B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel asymmetrically modified borohydride-based reducing agent and a method for producing the same. For more details, please refer to the general formula ()

[Formula] In the formula, R ₁ represents a lower alkyl group, a phenyl group that may be substituted with a lower alkoxy group, a naphthyl group, or a lower alkyl group. R ₂ represents a lower alkyl group, phenyl group, or alkoxycarbonyl group. R ₃ represents a hydrogen atom or a lower alkyl group. * means asymmetric carbon. The present invention relates to an asymmetrically modified borohydride reducing agent obtained by reacting an optically active amino alcohol represented by the formula or a salt thereof with an acid with a borohydride compound, and a method for producing the same. Boron reducing agents are used to produce optically active alcohol derivatives from ketone compounds. For example, the following general formula () is highly effective as an active ingredient in pesticide fungicides and plant growth regulators.

[Formula] [In the formula, R ₄ represents an alkyl group, a cycloalkyl group, or a cycloalkenyl group, or
Represents a phenyl group optionally substituted with a halogen atom, an alkyl group, a haloalkyl group, a cyano group, an alkoxyl group, a phenoxy group, or a phenyl group. R ₅ is an imidazol-1-yl group or 1,
Represents a 2,4-triazol-1-yl group.
R ₆ represents a t-butyl group, or 1, in which the benzene ring may be substituted with a halogen atom,
Represents a 1-dimethyl-2-phenylethyl group.
* means asymmetric carbon. ] It is used to produce the optically active α,β-unsaturated alcohol derivative shown below. Conventionally, 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.Perkin1, 371
(1978) using sodium borohydride as an optically active ephedrin onium salt. RF Borch et al., J.Org.Chem, 372347 (1972)
A method using an optically active amine borane complex described in . 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 (1983);
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 an asymmetrically modified borohydride reducing agent for obtaining an optically active alcohol derivative by asymmetrically reducing a ketone compound, and a method for producing the same. An asymmetrically modified borohydride-based reducing agent (hereinafter referred to as the compound of the present invention) obtained by reacting an optically active amino alcohol represented by the general formula () or its salt with an acid with a borohydride compound. I found it. The present invention will be explained in detail below. In the optically active amino alcohol represented by the general formula () which is a raw material for the compound of the present invention, specific examples of the substituent R ₁ include an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 5 to 10 carbon atoms, and a carbon Aralkyl group of number 7 to 16, or halogen atom,
Examples include a phenyl group which may be substituted with an alkyl group, a cyano group, an alkoxyl group or an alkoxycarbonyl group, or a naphthyl group which may be substituted with a halogen atom, an alkyl group, a cyano group, an alkoxyl group or an alkoxycarbonyl group. As a specific example of R ₂ , carbon number 6
~16 aryl group, alkyl group having 1 to 10 carbon atoms,
An aralkyl group having 7 to 16 carbon atoms, an alkyloxycarbonyl group having 1 to 10 carbon atoms in the alkyl moiety, and specific examples of R ₃ include a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 7 to 6 carbon atoms. ~16 aralkyl groups are mentioned. More specifically, the optically active amino alcohol represented by the general formula () includes optically active norephedrin, norpseudoephedrin, freonine 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-diethoxyphenyl)-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, 1-(2-methoxyphenyl)-2-amino-1-propanol, 1-(2
-ethoxyphenyl)-2-amino-1-propanol, 1-(2-propoxyphenyl)-2-amino-1-propanol, 1-(2-ethoxy-
5-methylphenyl)-2-amino-1-propanol, 1-(2-benzyloxyphenyl)-2
-Amino-1-propanol, 1-(2-methoxy-5-chlorophenyl)-2-amino-1-propanol, 1-(2,6-dimethoxyphenyl)
-2-amino-1-propanol, 1-(2,4,
6-trimethoxyphenyl)-2-amino-1-
Mention may be made of propanol or 1-α-naphthyl-2-amino-1-propanol. These are, for example, MJKalm.J.Org.Chem., 25 ,
1929-37 (1960); WH Hartung et al., J. Am. Chem.
Soc., 52 , 3317-22 (1930); WH Hartung et al.
J.Am.Chem.Soc., 51 , 2262-6 (1929); MC
Kloetzel et al., J.Org.Chem., 11 , 390-4 (1946)
It is manufactured by the method described in et al. Next, a method for producing the compound of the present invention will be described. When the borohydride compound is metal borohydride, the compound of the present invention can be obtained by reacting an acid and salt of an optically active amino alcohol represented by the general formula () with metal borohydride in a solvent,
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 the source of the optically active amino alcohol salts mentioned above 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. . Further, the salt may be used as the salt itself, or may be generated in advance from an optically active amino alcohol and an acid in the system during the production of the compound of the present invention. 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. In the production of the compound of the present invention, the molar ratio of the borohydride compound to the optically active amino alcohol is 0.7:1 to 2:1, preferably 0.7:1 when the borohydride compound is metal borohydride in terms of boron.
1 to 1.3:1, more preferably 1:1, and in the case of borane, 0.7:1 to 1.3:1, preferably 1:1. The solvent used in the production of the compound of the present invention 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- A halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 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 in combination to dissolve it. In addition, the reaction temperature is usually in the range of -78 to 100℃,
Preferably it is in the range of -40 to 100°C. Note that the reaction is usually carried out in an atmosphere of an inert gas such as nitrogen or argon. The compound of the present invention thus obtained may be used after being isolated from the reaction solution, but it is usually used in the reduction reaction as a solution without being isolated. Although the structure of the compound of the present invention has not necessarily been determined, it is presumed that the hydroxyl group and amino group of the optically active amino alcohol are bonded or coordinated to the boron of the borohydride compound. In addition, the compound of the present invention can be prepared by the general formula () by decomposing it with an alkaline aqueous solution.

[Formula] [In the formula, R ₁ , R ₂ , R ₃ and * have the same meanings as above. ] A compound represented by the following is obtained. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. Example 1 (+)-norehuedrine hydrochloride under nitrogen atmosphere
Suspend 0.338g in 5ml of deuterated chloroform at -30℃
Add a solution of 0.0681 g of sodium borohydride in 1 ml of dimethylformamide, and heat at 2°C from -30°C.
When the mixture was brought to room temperature over time, 87 ml of hydrogen gas was generated and a solution of the compound of the present invention was obtained. of this solution
The ^11B nuclear magnetic resonance spectrum (BF ₃ /OEt ₂ standard) was as follows. -20.95ppm, +7.21ppm Next, this solution was decomposed with a 2.5N aqueous sodium hydroxide solution. After washing the organic layer with water, it was purified by silica gel column chromatography using n-hexane-ethyl acetate (1/1) as a developing solution.
0.112g of crystals were obtained. ¹¹ B nuclear magnetic resonance spectrum −20.5ppm (BF ₃・
OEt ₂ standard) mp93~95℃ (decomposition), [α] _D +49.7°
(c=1.0, THF) This crystal was identified by X-ray diffraction as a borohydride compound having the following structure.

[Formula] Example 2 A solution of the compound of the present invention having the following physical properties was obtained in the same manner as in Example 1, except that hepta-deuterated dimethylformamide was used in place of dimethylformamide in Example 1. . ^1H nuclear magnetic resonance spectrum ( _CDCl3 −DMF− _d7 ,
δ (ppm)) 0.97(d), 1.04(d), 2.75~3.15(m), 3.1~3.5
(broad), 4.2-4.7 (broad), 5.18(d), 7.31(s) Examples 3-8 In Example 2, (+)-1-(2,5- dimethylphenyl)-2-amino-1-propanol hydrochloride,
(-)-1-α-naphthyl-2-amino-1-propanol hydrochloride, (+)-1-(2,5-dimethoxyphenyl)-2-amino-1-propanol hydrochloride, (+)- 1-(2,5-diethoxyphenyl)
-2-amino-1-propanol hydrochloride, (+)-
1-(2-methoxyphenyl)-2-amino-1-
The same procedure as in Example 2 was carried out except that propanol hydrochloride and (-)-1-(2-ethoxyphenyl)-2-amino-1-propanol hydrochloride were used.
A solution of the compound of the present invention having the physical properties shown in Table 1 was obtained.

[Table] Example 9 Under nitrogen atmosphere, (+)-norefuedrin was added to 1.8 ml (0.9 mmol) of 0.50 M diborane tetrahydrofuran solution and 2 ml of 1,2-dichloroethane solution.
A solution of 0.272 g (1.8 mmol) in 4 ml of 1,2-dichloroethane was added dropwise at -78°C, and the mixture was warmed to room temperature from -78°C in about 2 hours. The ¹¹ B nuclear magnetic resonance spectrum of this solution was as follows. −20.7ppm, +7.7ppm Reference Example Under nitrogen atmosphere, (+)-norephdrine hydrochloride
Suspend 0.338 g (1.8 mmol) in 5 ml of 1,2-dichloroethane, cool to -30°C, add 1 ml of dimethylformamide solution of 0.0681 g (1.8 mmol) of sodium borohydride, and suspend from -30°C for 2 hours. If the temperature is set to room temperature, 87ml of hydrogen gas will be generated.
Asymmetrically modified borohydride compounds were prepared. Next, this suspension was added to (E)-1-(2,4-diclophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3- On (E/Z=99.9/0.1) 0.39g (1.2 mmol)
A 4 ml solution of 1,2-dichloroethane was added at room temperature, and the mixture was stirred for 23 hours. Next, 6 ml of 2M hydrochloric acid was added and stirred for 2 hours, and the organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was purified with a 2 g column of silica gel using chloroform solvent and concentrated under reduced pressure to give 0.39 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4- Triazole-1-
yl)-4,4-dimethyl-1-pentene-3-
Crude crystals of ol were obtained, and analysis by gas chromatography showed that the reaction rate was 96.4%, and the composition of the reaction product was 98.3% E form and Z form (after the ketone compound isomerized to Z form, carbonyl group (return) was 1.7%. Optical rotation [α] _D -19.93° (c = 1.0, CHCl ₃ ) When the enantiomeric ratio of alcohol E form was analyzed by high performance liquid chromatography using an optically active column, the (-) form was 85.1% and the (+) form was 14.9%. It was hot.
Optical yield 70.2%.

Claims (1)

[Claims] 1 General formula () [Formula] [In the formula, R ₁ represents a lower alkyl group, a phenyl group, a naphthyl group, or a lower alkyl group which may be substituted with a lower alkoxy group. R ₂ represents a phenyl group, a lower alkyl group, or an alkoxycarbonyl group. R ₃ represents a hydrogen atom or a lower alkyl group. * means asymmetric carbon. ] Asymmetrically modified hydrogenation obtained by reacting a salt of an optically active amino alcohol represented by the formula with an acid and a metal borohydride, or by reacting an optically active amino alcohol represented by the general formula () with borane. Boron-based reducing agent. 2 General Formula () [Formula] [In the formula, R ₁ represents a lower alkyl group, a phenyl group, a naphthyl group, or a lower alkyl group which may be substituted with a lower alkoxy group. R ₂ represents a phenyl group, a lower alkyl group, or an alkoxycarbonyl group. R ₃ represents a hydrogen atom or a lower alkyl group. * means asymmetric carbon. ] Asymmetrically modified hydrogen characterized by reacting a salt of an optically active amino alcohol represented by the formula () with an acid and a metal borohydride, or reacting an optically active amino alcohol represented by the general formula () with borane. A method for producing a boron-based reducing agent.