JPH0645577B2 - Method for producing optically active amines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to a method for producing an optically active amine, and more specifically to the general formula (III) (In the formula, R ₆ and R ₇ represent an aryl group which may be substituted by an alkyl group, an aralkyl group which may be substituted by an alkyl group or an alkyl group, which are not the same). The present invention relates to a method for producing optically active amines.

<Prior Art and Problems to be Solved by the Invention> Optically active amines represented by the general formula (III) are important compounds as optical resolving agents such as pharmaceuticals, agricultural chemicals or intermediates thereof, It is also well known that a racemate is produced once and then optically resolved by using an optically active acid or the like (for example, Optical Resolution Procedures for Chemical
Compounds Vol 1).

The conventional method of producing optically active amines by optical resolution is to first produce a racemate, then act an optically active acid on this to form a salt, and utilize the difference in solubility of the produced diastereomeric salts. One diastereomeric salt is crystallized, the salt is then separated, and then the salt is decomposed by the action of an alkali to decompose and recover the optically active amine which is one of the antipodes. However, there are problems such as complicated operation and poor efficiency.

On the other hand, a method of asymmetrically reducing an oxime of an asymmetric ketone such as acetophenone to synthesize an optically active amine has also been attempted. For example, J. Chem. Soc., Perkin I 1902 (1974) describes a method using an asymmetric reducing agent obtained from optically active glucofuranose and lithium aluminum hydride.
m.Soc., Perkin I 2039 (1985) reported a method using an asymmetric reducing agent obtained from an optically active α, α-diphenyl-β-amino alcohol and a borohydride compound.

However, the former method has a problem that the optical yield is low, and the latter method has a chiral auxiliary, that is, the optically active α, α.
In addition to the problem that it is not always industrially easy to obtain -diphenyl-β-amino alcohols, R and S
In the case of producing an optically active amine having the absolute configuration of, it is considered that a chiral auxiliary having an absolute configuration corresponding to each is required, and two kinds of optically active α, α-diphenyl of R and S. There is a problem that it is necessary to always prepare -β-amino alcohol.

<Means for Solving Problems> In order to solve the above-mentioned various problems, the present inventors have earnestly studied a method for producing an optically active amine by asymmetric reduction of an oxime of an asymmetric ketone, and as a result, a general formula The optically active α, α-diphenyl-β-amino alcohols represented by (I) are effective as a chiral auxiliary, and the compound is industrially easily available, and the compound and a borohydride compound are also available. It was found that the reducing agent obtained from the above can easily give an optically active amine in a high optical yield, and an optically active alcohol of R and S can be optionally used by using an asymmetric auxiliary agent of R or S. I found a way to make different.

That is, the present invention is represented by the general formula (I) (In the formula, R ₁ and R ₂ represent a hydrogen atom, an alkyl group or an alkoxyl group, R ₃ represents a hydrogen atom or an alkyl group, and R ₄ represents an alkyl group.) And an optically active amino alcohol and borohydride. The asymmetric reducing agent obtained from the compound is represented by the general formula (II) (In the formula, R ₅ represents an alkyl group, an aralkyl group or an alkyl-substituted silyl group. R ₆ and R ₇ are an aryl group which may be substituted with an alkyl group, and an aralkyl group which may be substituted with an alkyl group. Groups, or alkyl groups, which are not the same, are reacted with an anti-form or a syn-form of the oxime derivative represented by, or a mixture rich in either of them, and the anti-form or the anti-form is rich. From the mixture, the absolute configuration of the amino-substituted carbon of the optically active aminoalcohol (I) is identical to the absolute configuration of the amino-substituted carbon of the syn or syn-rich mixture. The general formula (II
I) (In the formula, R ₆ and R ₇ have the same meanings as described above.) The present invention provides a method for producing an optically active amine.

The present invention will be described in detail below.

The optically active amino alcohol used in the present invention has the general formula
Examples of the substituents R ₁ and R ₂ on the benzene ring include those represented by (I), for example, a hydrogen atom, methyl,
Examples thereof include lower alkyl groups such as ethyl, propyl, pentyl, pentyl and hexyl, lower alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy, and the substitution position thereof is not particularly limited.

R ₃ is, for example, hydrogen atom, methyl, ethyl,
Lower alkyl groups such as propyl, butyl, pentyl, hexyl and the like, and examples of R ₄ include lower alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl and the like. More specific compounds include, for example, optically active norephedrine, ephedrine, 2-amino-1- (2-methylphenyl) -1-propanol 2-amino-1- (2-ethylphenyl) -1- Propanol 2-amino-1- (2-methoxyphenyl) -1-propanol 2-amino-1- (2-ethoxyphenyl) -1-propanol 2-amino-1- (2,5- Dimethylphenyl) -1-
Propanol 2-amino-1- (2,5-diethylphenyl) -1-
Propanol 2-amino-1- (2,5-dimethoxyphenyl) -1
-Propanol 2-amino-1- (2,5-diethoxyphenyl) -1
-Propanol 2-amino-1- (2-methoxy-5-methylphenyl) -1-propanol 2-amino-1-phenyl-1-butanol 2-amino-1- (2-methylphenyl ) -1-Butanol 2-amino-1- (2-ethylphenyl) -1-butanol 2-amino-1- (2-methoxyphenyl) -1-butanol 2-amino-1- ( 2-Ethoxyphenyl) -1-butanol 2-amino-1- (2,5-dimethylphenyl) -1-
Butanol 2-amino-1- (2,5-diethylphenyl) -1-
Butanol 2-amino-1- (2,5-dimethoxyphenyl) -1
-Butanol 2-amino-1- (2,5-diethoxyphenyl) -1
-Butanol 2-amino-1- (2-methoxy-5-methylphenyl) -1-butanol 2-amino-1-phenyl-1-pentanol 2-amino-1- (2,5- Dimethylphenyl) -1-
Pentanol 2-amino-1- (2,5-dimethoxyphenyl) -1
-Pentanol 2-amino-1-phenyl-1-hexanol 2-amino-1-phenyl-1-heptanol 2-amino-1-phenyl-1-octanol and the like.

The present invention uses an asymmetric reducing agent obtained from an optically active amino alcohol (I) and a borohydride compound as described above. Examples of the borohydride compound include lithium borohydride and sodium borohydride. And boranes such as alkali metal borohydride, diborane, borane dimethyl sulfide complex, borane tetrahydrofuran complex and the like. The amount used is an optically active amino alcohol
It is usually 1 to 4 mole times, preferably 2 to 3 mole times, relative to (I).

In preparing the asymmetric reducing agent, ethers such as diethyl ether, tetrahydrofuran, dioxane, diglyme, etc. as a solvent, hydrocarbons such as benzene, toluene, xylene, chlorobenzene, chloroform, 1,2-
A halogenated hydrocarbon such as dichloroethane or a mixed solvent thereof is usually used.

When an alkali metal borohydride is used as the borohydride compound, it is usually suspended or dissolved in a solution of the optically active amino alcohol (I), and then a mineral acid such as hydrogen chloride or boron fluoride. An asymmetric reducing agent is prepared by adding a Lewis acid such as boron chloride. The amount of acid used is usually 0.8 with respect to alkali metal borohydride.
˜2 mol times, preferably 0.9 to 1.5 mol times.

When boranes are used as the borohydride compound, the asymmetric reducing agent can be prepared by adding it to a solution of the optically active amino alcohol (I). The preparation temperature is usually 100 ° C. or lower, preferably 20 ° C. or lower regardless of which borohydride compound is used.

The present invention provides a chiral reducing agent thus obtained by the general formula (II)
The anti-form or syn-form of the oxime derivative represented by the formula (5) is reacted with a mixture rich in either of these forms.
Examples of ₅ include methyl, ethyl, propyl, butyl,
Pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, cyclooctyl, nonyldecyl and the like alkyl having 1 to 10 carbon atoms, benzyl, β-phenethyl, naphthylmethyl and the like 7 to 1 carbon atoms
1 aralkyl group, trimethylsilyl, dimethyl-t-
Butylsilyl, tri-n-propylsilyl, tri-n-
Examples thereof include an alkylsilyl group having 3 to 12 carbon atoms such as butylsilyl.

Examples of R ₆ and R ₇ include phenyl, o-, and m.
-, P-methylphenyl, o-, m-, p-ethylphenyl, o-, m-, p-propylphenyl, 2,3-,
2,4-, 2,5-, 2,6-dimethylphenyl, α-
Aryl groups such as naphthyl and β-naphthyl groups, alkylaryl groups and methyl, ethyl, propyl, butyl,
Lower alkyl groups such as pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, o-, m-, p-tolylmethyl, (o-, m-, p-ethylphenyl) methyl, (2,3-, 2,4-, 2,5-, 2,6-dimethylphenyl) methyl, 2-phenylethyl, 2- (o
-, M-, p-tolyl) ethyl, (2,3-, 2,4
-, 2,5-, 2,6-dimethylphenyl) ethyl, 3
Examples include aralkyl groups such as -phenylpropyl and alkyl-substituted aralkyl groups.

More specific compounds include, for example, acetophenone, propiophenone, butyrophenone, isobutyrophenone,
α-acetonaphthone, β-acetonaphthone, phenylbenzyl ketone, phenyl (p-tolylmethyl) ketone,
Phenyl (m-tolylmethyl) ketone, phenyl (o-
Tolylmethyl) ketone, phenyl (2-phenylethyl) ketone, 2-butanone, 2-pentanone, 2-hexanone, 3-hexanone, 2-heptanone, 3heptanone, 3-octanone, cyclohexylmethylketone, cyclohexylethylketone, α- Phenylacetone, 2
-O-methyl, o-octyl, o-cyclohexyl, o-, such as phenylethylmethylketone, 2-phenylethylethylketone, 3-phenylpropylmethylketone
Examples include oximes such as benzyl and o-trimethylsilyl, and syn- and anti-forms thereof and a mixture rich in one of these.

These ketone oximes can be easily produced from the corresponding ketone by a known method. When one of the syn-form or the anti-form is used, the remaining separated isomer can be converted into the necessary isomer again by performing a syn / anti isomerization reaction by a known method, and the raw material can be used effectively. obtain.

In reacting the above-mentioned reducing agent with oximes (II),
As the solvent to be used, ethers such as diethyl ether and tetrahydrofuran, hydrocarbons such as benzene, toluene and xylene, chlorobenzene, chloroform and 1,2-
Examples thereof include halogenated hydrocarbons such as dichloroethane and the like, or mixed solvents thereof.
It is usually 2 to 50 times the weight of I). The reducing agent used is an optically active amino alcohol for oximes (II).
The amount is usually 1 to 6 mol times, preferably 1 to 3 mol times in terms of (I), and the reaction temperature is usually 100 ° C. or less, preferably −
It is 20-40 degreeC.

The progress of the reaction can be confirmed by an analytical means such as gas chromatography.

After the completion of the reaction, the reducing agent is deactivated by adding a mineral acid such as hydrochloric acid, then made alkaline with caustic soda and the like and extracted with a solvent such as toluene to obtain the optically active amines of interest (III ) And an optically active aminoalcohol (I) used as a chiral auxiliary, and then an ordinary separation means such as distillation is used to obtain the desired product.

When R ₆ of the objective optically active amine (III) has an aryl group and R ₇ has an aralkyl group, the objective compound (III) and a chiral auxiliary ( I) can be separately and sequentially separated and recovered. For example pH 8.5
The target compound (III) can be selectively recovered by adjusting the pH to 9.5, and then the chiral auxiliary (I) can be selectively recovered by adjusting the pH to 11 or more.

Further, by using the solubility difference between the target compound (III) and the asymmetric auxiliary agent (I) by using hexane or the like instead of the toluene as the extraction solvent, the target compound (I
II) can also be selectively recovered.

The target product (III) obtained by the above method can be further purified by a purification means such as distillation or column chromatography.

<Effects of the Invention> Thus, the desired optically active amines (III) are produced, but according to the method of the present invention, the optical activity of R and S can be obtained only by using one asymmetric auxiliary agent of R or S. Amine can be easily made separately. For example, in the case of a chiral auxiliary of R, R
The optically active amine of interest can be obtained by using an anti oxime ether if the optically active amine of 1 is required, and by using an oxime ether of the syn if the optically active amine of S is required.

Further, according to the present invention, an optically active amine of either R or S can be obtained from both the anti-form and the syn-form of oxime ether by using an asymmetric auxiliary of R and S. For example, when an optically active amine of R is required, the objective is easily achieved by combining an antioxime ether and an asymmetric auxiliary of R, and combining an oxime ether of a syn and an asymmetric auxiliary of S. You can do it.

In addition to the above, the present invention brings various advantages such as a high optical yield of a target product and the availability of an asymmetric ligand to be used.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 A solution of erythro- (l) -2-amino-1- (2,5-dimethoxyphenyl) -1-propanol 70 mg (0.33 mmol) in tetrahydrofuran (THF) was cooled to -70 ° C and borane 0.66 was added. After adding a mmol of THF solution dropwise, the temperature was gradually raised to room temperature.

Then, 50.2 mg (0.21 mmol) of anti-phenyl (p-tolylmethyl) ketone (o-methyloxime) in TH
The solution F was added dropwise, and the mixture was stirred at room temperature for 12 hours, then heated to 60 ° C. and stirred at the same temperature for 5 hours.

Next, 18% hydrochloric acid was added, the mixture was stirred at the same temperature for 1 hour, and then concentrated under reduced pressure. Then, after adding an aqueous solution of caustic soda to make the mixture alkaline, extraction is performed by adding toluene, and the obtained organic layer is concentrated and purified with an alumina column to obtain optically active 1-phenyl-2- (p-tolyl) ethylamine. It was

The optical purity was measured by liquid chromatography using an optically active column.

The optical yield is 94%, the absolute configuration is S, and the yield is 68.
%Met.

(1) -Norephedrine 1.26 g (8.3 mmol) TH
The F solution was cooled to −70 ° C., a THF solution containing 16.6 mmol of borane was added dropwise thereto, and the temperature was gradually raised to room temperature.

Then anti-phenyl (p-tolylmethyl) ketone (o-methyloxime) 0.67 g (2.8 mmol) THF
The solution was added dropwise, and the mixture was stirred at room temperature for 12 hours, then heated to 60 ° C. and stirred at the same temperature for 5 hours.

Next, 18% hydrochloric acid was added, the mixture was stirred at the same temperature for 1 hour, and then concentrated under reduced pressure. Then add caustic soda solution to obtain pH =
After adjusting to 9.1, toluene was added for extraction, and the obtained organic layer was concentrated to give 1-phenyl-2-
(P-Tolyl) ethylamine was obtained.

Optical yield is 94%, absolute configuration is S, yield is 61%
Met.

Example 3 A THF solution of 278 mg (1.84 mmol) of (1-)-norefuedrin was cooled to -30 ° C, and 4 mmol of dimethyl sulfide complex of borane was added dropwise thereto, and then the temperature was gradually raised to room temperature.

Then, a solution of 183 mg of anti-2-acetone naphthone-o-methyloxime in THF was added, and the mixture was stirred at room temperature for 20 hours.
The mixture was stirred at 0 ° C for 5 hours. Next, 18% hydrochloric acid was added to this, and the mixture was stirred at the same temperature for 1 hour, and then chloroform was added to separate the layers.

The separated aqueous layer was basified by adding an aqueous sodium hydroxide solution, extracted with hexane, and the separated hexane layer was concentrated to obtain 1- (2-naphthyl) ethylamine.

The optical yield is 92%, the absolute configuration is S, and the yield is 7
It was 8%.

Example 4 In Example 2, 16.6 mmol of borane dimethyl sulfide complex was used instead of borane, and 1 was used instead of THF.
1-Phenyl-2- (p-tolyl) ethylamine was obtained in the same manner as in Example 2 except that 2-dichloroethane was used.

The optical yield is 91%, the absolute configuration is S, and the yield is 6
It was 3%.

Examples 5 to 13 Table 1 shows the results when various substrates were changed. Examples 5 to 8 were based on Example 2, and Examples 9 to 13 were based on Example 3.

Example 14 To a solution of 163 mg (1.08 mmol) of (mono) -norephedrine in THF was added 92 mg (2.48 mmol) of sodium borohydride, the mixture was cooled to -65 ° C, and 460 mg (3.24 mmol) of boron trifluoride etherate was added dropwise. The temperature was raised to 20 ° C. over about 3 hours. Then, a solution of 115 mg (0.48 mmol) of anti-phenyl (p-tolylmethyl) ketone (o-methyloxime) in THF was added dropwise thereto.
After stirring for 12 hours at 0 ° C., the temperature was raised to 60 ° C. at the end and stirred for 5 hours at the same temperature.

Next, 18% hydrochloric acid was added, the mixture was stirred at the same temperature for 1 hour, and then concentrated under reduced pressure. Then, after adding a caustic soda aqueous solution to make it alkaline, toluene was added for extraction, and the obtained organic layer was concentrated and purified with an alumina column to obtain an optically active 1
-Phenyl-2- (p-tolyl) ethylamine was obtained.

The optical yield is 81%, the absolute configuration is S, and the yield is 4
It was 1%.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07C 211/30 9280-4H

Claims (1)

[Claims] 1. A general formula (I) (In the formula, R ₁ and R ₂ represent a hydrogen atom, an alkyl group or an alkoxyl group, R ₃ represents a hydrogen atom or an alkyl group, and R ₄ represents an alkyl group.) And an optically active amino alcohol and borohydride. The asymmetric reducing agent obtained from the compound is represented by the general formula (II) (In the formula, R ₅ represents an alkyl group, an aralkyl group or an alkyl-substituted silyl group. R ₆ and R ₇ are an aryl group which may be substituted with an alkyl group, and an aralkyl group which may be substituted with an alkyl group. Group, or an alkyl group, which cannot be the same), is reacted with either the syn-form or the anti-form of the oxime derivative represented by, or a mixture rich in either of them, and is rich in the anti-form or the anti-form. From the amino acid-substituted carbon of the optically active aminoalcohol (I), which is the same as the absolute configuration of the amino-substituted carbon of the syn-form or the syn-rich mixture. Is a general formula (III) having the opposite absolute configuration (In the formula, R ₆ and R ₇ have the same meanings as described above.)