JPH09157228A - Method for producing optically active amines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as a synthetic intermediate for a medicine, a reagent for optical resolution, by using a catalyst high in generality, activity and selectivity and subjecting an imine compound to a hydrogen transfer type asymmetric reduction. SOLUTION: This optically active amine is produced by subjecting an imine compound to a hydrogen transfer type asymmetric reduction in the presence of a transition metal complex, an optically active nitrogen-containing compound and a hydrogen donative organic or inorganic compound. A compound of formula I (R<1> is an aromatic monocyclic or polycyclic hydrocarbon, an alicyclic hydrocarbon, a cyclic hydrocarbon, etc.; R<2> and R<3> are each H, an aromatic hydrocarbon, etc.) is especially preferable as the imine compound. A compound of formula II is preferable as the optically active amine. A metal complex of a metal of the group VIII (e.g. a compound of formula III) is preferable as the transition metal complex. An optically active amine derivative is preferable as the optically active nitrogen-containing compound. An alcohol compound, formic acid, a formate, a hydrocarbon compound, a heterocyclic compound, hydroquinone or phosphorous acid is preferable as the hydrogen donative organic or inorganic compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active amines. More specifically, the present invention relates to a novel method for producing optically active amines useful for various purposes such as pharmaceutical synthetic intermediates and optical resolving agents, which are excellent in practicality.

[0002]

2. Description of the Related Art Conventionally, as a method for synthesizing an optically active amine, a method of once producing a racemic compound and optically resolving it using an optically active acid or an asymmetric synthesis method has been known. Has been. In the optical resolution method, an optically active acid or the like is required in an equivalent amount or more with respect to the amine compound, and complicated operations such as crystallization, separation and purification are required to obtain the optically active amine compound. 1) as an asymmetric synthesis method
A method using an enzyme, 2) a method using a metal hydride,
3) A method of asymmetric hydrogenation using a metal complex catalyst is known. Particularly in the method 2), many methods have been reported in which the carbon-nitrogen multiple bond is asymmetrically reduced using an asymmetric metal hydride. For example (1) Comprehensive
Organic Synthesis Eds BM Trost and I. Fleming Vo
l.8, page 25 (1991), (2) Organic Preparatio
n and Procedures Inc. O. Zhu, RO Hutchins, and
MK Huchins Vol.26 (2), pp. 193-235, (199
4) and (3) The method of stoichiometric reduction of an imine compound or an oxime compound described in JP-A-2-311446 using a metal hydride having an optically active ligand is known as a general method. Has been. However, although this method has many excellent reaction selectivity, it is necessary to use an equivalent amount or more of the reaction agent with respect to the reaction substrate.
It has a drawback that it requires a post-reaction neutralization treatment and is not practical as a method for synthesizing optically active amines in a large amount due to complicated purification of optically active substances. Further, in the method of 3) above, a method for asymmetric hydrogenating carbon-nitrogen multiple bonds using a metal complex catalyst is described in Asymmetric Catalysis In Organic.
Synthesis, pp. 82-85 (1994) Ed. R. Noyori
Although a method for asymmetric hydrogenation of an imine compound having a functional group by an optically active metal complex catalyst described in detail in Section 1 is known, it is not practical from the viewpoint of reaction rate and selectivity.

On the other hand, the method using an enzyme can obtain an amine having a relatively high optical purity, but the reaction substrate is limited, and the absolute configuration of the obtained amine is also limited to a specific one. In addition, the method using the asymmetric hydrogenation metal complex catalyst of a transition metal is that there is still no method for producing optically active amines with high selectivity, and a pressure resistant reactor is required because hydrogen gas is used as a hydrogen source. There are difficulties in terms of operability and safety.

Therefore, it has been desired in the past to realize a new synthetic method using a highly general, highly active and highly selective catalyst for producing an optically active amine.

[0005]

In order to solve the above problems, the present invention provides an imine compound containing hydrogen in the presence of a transition metal complex, an optically active nitrogen-containing compound, and a hydrogen-donating organic or inorganic compound. Provided is a method for producing an optically active amine, which comprises producing an optically active amine by a mobile asymmetric reduction.

Further, according to the present invention, in the above method, the following general formula (a)

[0007]

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(R ¹ may have a substituent, an aromatic monocyclic or aromatic polycyclic hydrocarbon group, or a saturated or unsaturated aliphatic group which may be unsubstituted or may have a substituent. A hydrocarbon group or a cyclic hydrocarbon group, or a heteromonocyclic or heteropolycyclic group containing a hetero atom such as nitrogen, oxygen, or a sulfur atom, and R ² and R ^{3 each} have hydrogen or a substituent Which may be a saturated or unsaturated chain or cyclic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, R ³ may be a hydroxyl group or the above organic group bonded via an oxygen atom, R ¹ and R ² , R ¹ and R ³ or R ² and R ³ may combine to form a ring, and asymmetrically reduces the imine compound represented by the general formula (b).

[0009]

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A process for producing an optically active amine, which comprises producing an optically active amine represented by the formula (R ¹ , R ² and R ³ represent the same organic groups as described above). Furthermore, according to the present invention, the above-mentioned transition metal metal complex is a group VIII transition metal, for example, a metal complex having an optically active ligand, and the optically active compound as the nitrogen-containing asymmetric compound is an optically active amine. One of the aspects is that it is a derivative.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is configured as described above, and the embodiments thereof will be further described below. First, the type of imine compound, which is a raw material compound of the present invention, is not particularly limited.

For example, this imine compound can be represented by the above general formula (a), but is not necessarily limited thereto. Looking at general formula (a), R
¹ is an unsubstituted or substituted aromatic monocyclic or polycyclic aromatic hydrocarbon group, an unsubstituted or substituted, saturated or unsaturated aliphatic hydrocarbon group or cyclic hydrocarbon Or a heteromonocyclic or polycyclic group containing a hetero atom such as nitrogen, oxygen or sulfur atom, and specifically, a phenyl group, 2-methylphenyl, 2-ethylphenyl, 2-isopropylphenyl, 2 -Tert-butylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 2-vinylphenyl, 3-methylphenyl, 3-ethylphenyl, 3-isopropylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 3-vinylphenyl, 4 -Methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl,
4-vinylphenyl, cumenyl, mesityl, xylyl,
1-naphthyl, 2-naphthyl, anthryl, phenanthryl, aromatic monocyclic and polycyclic groups such as indenyl group, cenyl, furyl, pyranyl, xanthenyl, pyridyl,
Examples thereof include heteromonocyclic and polycyclic groups such as pyrrolyl, imidazolinyl, indolyl, carbazoyl, phenanthronylyl and ferrocenyl groups. As in these examples, the substituent may have various arbitrary ones, such as hydrocarbon groups such as alkyl, alkenyl, cycloalkyl and cycloalkenyl, halogen atom, alkoxy group, carboxyl group, ester group and the like. May be oxygen-containing groups, nitro groups, cyano groups and the like.

Further, R ² and R ³ represent a hydrogen atom, a saturated or unsaturated hydrocarbon group, an allyl group, or a functional group containing a hetero atom, such as methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl. And an alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unsaturated hydrocarbons such as vinyl and allyl, and the same as the above R ¹ . R ³ represents hydrogen, a saturated or unsaturated hydrocarbon group, an allyl group or a functional group containing a hetero atom, and examples thereof include alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl, cyclopropyl and cyclobutyl. , A cycloalkyl group such as cyclopentyl and cyclohexyl, benzyl,
Examples include groups such as unsaturated hydrocarbons such as vinyl and allyl. Further, a saturated or unsaturated cyclic imine compound formed by combining R ¹ and R ² , R ¹ and R ³ , or R ² and R ³ can be exemplified.

Acyclic imine compounds can be easily synthesized from the corresponding ketones. In this case, a syn- and anti-form or a mixture rich in one of these syn- and anti-forms is used, but it should be purified from the mixture and used alone, or as a mixture of different imine compounds. You can also Furthermore, in the present invention, an oxime derivative having a carbon-nitrogen double bond can be used as a reaction substrate. In this case, a compound in which R ³ is a hydroxyl group is exemplified.

In the present invention, the above-mentioned transition metal complex constitutes an asymmetric reduction catalyst together with an optically active amine derivative. Among these transition metal complexes, various transition metals have a ligand. It is used as a compound having a particularly preferred formula (c)

[0016]

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(M is iron, cobalt, nickel, ruthenium, rhodium, iridium, osmium, palladium,
It is a Group VIII transition metal such as platinum, X represents hydrogen, a halogen atom, a carboxyl group, a hydroxy group, an alkoxy group, etc., and L represents a neutral ligand such as an aromatic compound or an olefin compound. m and n represent integers. ) Are used to form an asymmetric catalyst by using a transition metal complex represented by the formula (1) together with an optically active amine derivative. As described above, it is preferable that M ¹ in the transition metal complex represented by the general formula (c) is a transition metal of Group VIII such as iron, cobalt, nickel, ruthenium, rhodium, iridium, osmium, palladium and platinum. And even ruthenium is one of the desirable ones.

The aromatic compound as the neutral ligand is, for example, a monocyclic aromatic compound represented by the following general formula (d). Here, R ^{3 to} R ⁸ are the same or different substituents, and can represent hydrogen, a saturated or unsaturated hydrocarbon group, an allyl group, or a functional group containing a different atom. For example, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and heptyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
A group such as unsaturated hydrocarbon such as benzyl, vinyl and allyl, and a functional group containing a hetero atom such as hydroxyl group, alkoxy group and alkoxycarbonyl group can be shown. The number of the substituents is any number from 1 to 6, and the place can be selected arbitrarily.

[0019]

[Chemical 6]

The amount of the group VIII or other transition metal complex used in the present invention varies depending on the size of the reaction vessel, its form or economy, but is approximately in molar ratio with respect to the imine compound as the reaction substrate. 1/100 to 1/100,
000 can be used, preferably 1/200 to 1 /
The range is 5,000. In addition, in the present invention, an optically active nitrogen-containing compound is used in the asymmetric catalyst system.
It is presumed that it exists and acts as an asymmetric ligand for the transition metal complex. Such an optically active nitrogen-containing compound can also be exemplified as an “optically active amine compound” in the most expressive way. This optically active amine compound has, for example, the following general formula (e)

[0021]

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(R ⁹ , R ¹⁰ , R ¹⁵ and R ¹⁶ are hydrogen or a saturated or unsaturated hydrocarbon group, an aryl group, a urethane group or a sulfonyl group, and R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are these groups. The same or different groups such that the carbons to which the substituents are attached are asymmetric centers, hydrogen or alkyl groups, aromatic monocyclic and polycyclic groups, saturated or unsaturated hydrocarbon groups, and cyclic groups An optically active diamine compound represented by a hydrocarbon group). For example, as such a compound, optically active 1,2-diphenylethylenediamine, 1,2-cyclohexanediamine, 1,2
-Cycloheptanediamine, 2,3-dimethylbutanediamine, 1-methyl-2,2-diphenylethylenediamine, 1-isobutyl-2,2-diphenylethylenediamine, 1-isopropyl-2,2-diphenylethylenediamine, 1-methyl-2 , 2-di (p-methoxyphenyl) ethylenediamine, 1-isobutyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-isopropyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-benzyl- 2,2-di (p-methoxyphenyl) ethylenediamine, 1-methyl-2,2-dinaphthylethylenediamine, 1-isobutyl-2,2-
Dinaphthylethylenediamine, 1-isopropyl-2,
An optically active diamine compound such as 2-dinaphthylethylenediamine and an optically active diamine compound in which one or two of the substituents of R ⁹ to R ¹⁵ are a sulfonyl group, an acyl group or a urethane group can be used. Further, preferably, an optically active diamine compound having one sulfonyl group can be used. Further, the optically active diamine that can be used is not limited to the exemplified optically active ethylenediamine derivative, and optically active propanediamine, butanediamine, and phenylenediamine derivatives can be used.

As the optically active amine compound, an optically active amino alcohol compound represented by the following general formula (f) can also be used.

[0024]

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Here, at least one of R ¹⁷ and R ¹⁸ is a hydrogen group, and the remaining one is hydrogen or a saturated or unsaturated hydrocarbon group, an aryl group, a urethane group or a sulfonyl group, and R ^{19 to} R ²² Are the same or different groups such that the carbon to which these substituents are bonded becomes an asymmetric center, hydrogen or an alkyl group, aromatic monocyclic and polycyclic groups, saturated or unsaturated hydrocarbon groups, and R ²³ is a cyclic hydrocarbon group and represents a hydrogen atom, an alkyl group, an aromatic monocyclic or polycyclic group, a saturated or unsaturated hydrocarbon group, and a cyclic hydrocarbon group. Further, any one group of R ¹⁹ and R ²⁰ may be bonded to any one group of R ²¹ and R ²² to form a ring, or any one group of R ¹⁷ and R ¹⁸ may be formed. And any one of R ²⁰ and R ²¹ may combine to form a ring. Specifically, the optically active amino alcohols shown in the examples below can be used. Further, as the optically active amine compound, the following general formula (g)
An aminophosphine compound represented by can be used.

[0026]

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Here, R ²⁴ and R ²⁵ are hydrogen or a saturated or unsaturated hydrocarbon group, an aryl group, a urethane group, a sulfonyl group, or an acyl group, and (CR ₂ ²⁶ ) _n has a substituent bonded thereto. The same or different groups such that the carbons present are asymmetric centers, hydrogen or alkyl groups, aromatic monocyclic and polycyclic groups, saturated or unsaturated hydrocarbon groups, and cyclic hydrocarbon groups, R ²⁷ and R ²⁸ represent hydrogen, a saturated or unsaturated hydrocarbon group, or an allyl group. Specifically, the optically active aminophosphines shown in the examples can be used.

For example, the amount of the optically active amine compound that can be exemplified as described above is approximately 0.5 to 20 equivalents, preferably 1 to 2 equivalents relative to the transition metal complex. The above-mentioned two components of the transition metal complex and the optically active amine compound used as a catalyst are essential components for smoothly proceeding the asymmetric reduction reaction and achieving a high asymmetric yield. If all the components are insufficient, an alcohol compound with sufficient reaction activity and high optical purity cannot be obtained.

Further, the hydrogen-donating organic or inorganic compound used in the method for producing optically active amines by hydrogen transfer asymmetric reduction in the present invention can donate hydrogen by thermal action or catalytic action. The compound means a compound, and the kind of the hydrogen-donating compound is not particularly limited, but preferable examples include methanol, ethanol, 1-propanol, and 2
-Alcohol compounds such as propanol, butanol, benzyl alcohol, formic acid and its salts, for example those consisting of combinations with amines, unsaturated hydrocarbons or heterocyclic compounds having partially saturated carbon bonds such as tetralin and decalin, hydroquinone or There are phosphorous acid and the like. Of these, alcohol compounds are preferred, and more preferably 2-
Propanol is exemplified. The amount of the organic compound used as the hydrogen source used is determined by the solubility and economic efficiency of the reaction substrate. Usually, the substrate concentration may be about 0.1 to 30% by weight depending on the type of substrate, but it is preferably 0.1 to 10% by weight. In addition,
When using formic acid or a combination of formic acid and an amine as a hydrogen source, no solvent may be used. When used, an aromatic compound such as toluene or xylene, a halogen compound such as dichloromethane, DMSO, DMF, acetonitrile or the like. The organic compounds of can be used.

In the present invention, hydrogen pressurization is not essentially required, but hydrogen pressurization may be used depending on the reaction situation. However, even in the case of pressurizing with hydrogen, the pressure may be about 1 atm to several atm because the catalyst system has extremely high activity.
The reaction temperature can be about -20 ° C to 100 ° C in consideration of economy. More practically, the reaction can be carried out near room temperature of 25-40 degrees. The reaction time varies depending on the reaction conditions such as the concentration of the reaction substrate, the temperature and the pressure, but the reaction is completed in a few minutes to 100 hours.

The metal complex used in the present invention can be mixed with the optically active amine compound before the reaction is started. However, an asymmetric metal complex can be previously synthesized by the following method and used. That is, for example, a ruthenium-arene complex, an optically active amine compound, and triethylamine are suspended in 2-propanol and heated and stirred under an argon stream, and the resulting reaction mixture is cooled to remove the solvent and recrystallized from an alcohol solvent. To obtain an asymmetric complex.

The method of the present invention will be described in more detail with reference to the following examples. The reaction substrates and asymmetric metal complexes that can be used as typical examples are shown in Tables 1 and 2.
Instrument analysis was based on the following models. NMR: JEOL GSX-400 / Varian G
emini-200 (1H-NMR standard sample: TM
S, 31P-NMR standard sample: phosphoric acid) GLC: SHIMAZU GC-17A (column)
n: chiral CP-Cyclodextrin-
b-236-M19) HPLC: JASCO GULLIVER (column)
un: CHIRALCEL OJ, OB-H, OB, O
D) The absolute configuration of the obtained optically active amine compound is optical rotation, H
It was determined by PLC and X-ray structural analysis. Blank is unknown.

[0033]

[Table 1]

[0034]

[Table 2]

Example 1 6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline (Table 1-2a) (1.03 g, 5 mmol)
And ruthenium catalyst (Table 2) (R, R) -1a (16m
g, 0.025 mmol) to acetonitrile (10 m
After dissolving in L), a formic acid-triethylamine mixture (5: 2) was added and stirred at 28 ° C. for 3 hours. Aqueous sodium carbonate solution was added to the reaction mixture, and the product was extracted with ethyl acetate. 1H-N for those obtained by removing the solvent
MR (CDCl ₃ ) was measured and the conversion rate was calculated. Next, this was purified by silica gel chromatography, and the optical purity and absolute configuration of the obtained optically active amine were determined by HPLC or GLC. As summarized in Table 3, (S) -6,7-dimethoxy-1-methyl-1,
2,34-Tetrahydroisoquinoline (1.02 g, 9
9% yield, 96% ee) was obtained. Examples 2 to 28 The same reaction apparatus and the same experimental procedure as in Example 1 were used, and the reaction substrate, catalyst, reaction solvent, and reaction substrate / catalyst ratio were changed, and the obtained results are summarized in Table 3. Example 29 When an enamine compound was used by using the same reaction apparatus and the same experimental procedure as in Example 1, the reaction proceeded smoothly and the corresponding optically active amine compound was obtained. The results obtained are summarized in Table 3. Comparative Example 1 When a ruthenium-arene complex having no optically active amine ligand was used as a catalyst under the same conditions as in Example 1, the reaction proceeded and a racemic amine compound was quantitatively obtained. Comparative Example 2 When a ruthenium-arene complex without an optically active amine ligand was used as a catalyst under the same conditions as in Example 10, the reaction did not proceed at all.

[0036]

[Table 3]

[0037]

INDUSTRIAL APPLICABILITY As described in detail above, according to the present invention, it is possible to obtain an amine having an optical characteristic with a high yield and a high optical purity.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 209/08 C07D 209/08 211/86 211/86 217/02 217/02 495/04 111 495 / 04 111 // C07B 61/00 300 C07B 61/00 300 (71) Applicant 593182015 Hashiguchi Shohei 4-302 Kamisha, Meito-ku, Aichi Prefecture Nagoya City (302) Inventor Takao Ikariya, Shigetani-cho, Chikusa-ku, Aichi Prefecture 8-1 Chaya Kazaka Coaters 907 (72) Inventor Nobuyuki Uematsu 101 Arkanchel B205 101, Yanagitsubocho, Seto City, Aichi Prefecture Inventor Shohei Hashiguchi 4-302 (72) Inventor, Meito-ku, Nagoya City, Aichi Prefecture Akio Fujii 1505 Todaya, Nagakute-cho, Aichi-gun, Aichi Prefecture Habitation 3-B (72) Inventor Ryoji Noyori Nitta 135-417, Umemori-cho, Nisshin-shi, Aichi Prefecture

Claims (5)

[Claims] 1. An optically active amine is produced by subjecting an imine compound to hydrogen transfer asymmetric reduction in the presence of a transition metal complex, an optically active nitrogen-containing compound, and a hydrogen-donating organic or inorganic compound. And a method for producing optically active amines. 2. A compound represented by the general formula (a): (R ¹ is an aromatic monocyclic or aromatic polycyclic hydrocarbon group which may have a substituent, an unsubstituted or saturated aliphatic hydrocarbon group which may have a substituent) Or a cyclic hydrocarbon group, or a heteromonocyclic or heteropolycyclic group containing a hetero atom such as nitrogen, oxygen or sulfur atom, R
² and R ³ represent a hydrogen atom, or a saturated or unsaturated chain or cyclic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have a substituent. R ³
May be a hydroxyl group or the above-mentioned organic group bonded through an oxygen atom, and R ¹ and R ² , R ¹ and R ³ or R ² and R
³ may combine with each other to form a ring. A) an imine compound represented by the general formula (b): (R ¹ , R ² and R ³ represent the same organic groups as above.)
The method according to claim 1, wherein the optically active amines represented by 3. The method according to claim 1, wherein the transition metal complex is a metal complex of a Group VIII metal. 4. The method according to claim 1, wherein the optically active nitrogen-containing compound is an optically active amine derivative. 5. The method according to claim 1, wherein the hydrogen-donating organic or inorganic compound is an alcohol compound, formic acid, formate salt, hydrocarbon compound, heterocyclic compound, hydroquinone or phosphorous acid.