JP2001002610A - Production of optically active alcohol and transition metal complex - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a practical production process for optically active alcohol that uses only an optically active amine as an asymmetric source and other readily available compound as a catalyst source. SOLUTION: In the presence of a mixture of a trivalent phosphorus compound having no asymmetric center in its molecule, a transition metal compound and an optically active amine or a product (a transition metal complex) obtained from the mixture, a carbonyl compound represented by the formula: Ra-CO-Rb [Ra and Rb differs from each other, and are each a (substituted) alkyl group, a (substituted) alkenyl group, a (substituted) cycloalkyl group, a (substituted) aralkyl group, or a (substituted) aryl group] is allowed to react with hydrogen to produce the objective optically active alcohol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION Optically active alcohols are useful as synthetic intermediates for pharmaceuticals and agricultural chemicals, liquid crystal materials, and the like. The present invention relates to a method for producing optically active alcohols which is excellent in practicality, and a transition metal complex used as an asymmetric reduction catalyst in the production method.

[0002]

2. Description of the Related Art Known methods for producing optically active alcohols include 1) a method using enzymes such as baker's yeast, and 2) asymmetric hydrogen reduction of carbonyl compounds using a metal complex catalyst or the like. I have.

[0003] As the method 2), for example, (1) As
ymmetric Catalysis in Org
anic Synthesis. , Pp56-82 (1
994). Ed. R. Noyori,
Asymmetric hydrogenation method of a carbonyl compound having a functional group using an optically active transition metal complex catalyst, (2) Chem. Re
v. , 9 , 1051 (1992). It is described in,
A method by an asymmetric hydrogen transfer type reduction reaction using an asymmetric complex catalyst of Ru, Rh and Ir, (3) Oil Chemistry, pp882-83
1 (1980) and Advances in Catal
ysis. , 32 , 215 (1983). Ed. Y. I
asymmetric hydrogenation method using a Ni catalyst having a ligand modified with tartaric acid described in Zumi, (4) A
symmetric Syntheses. , 5 , Chapter 4 (1985). Ed. J. D. A method by asymmetric hydrosilylation described in Morrison, (5)
J. Chem. Soc. Perkin Trans. I
I, 2039 (1985); Am. Chem. S
oc. , 109 , 5551 (1987), a method for reducing borane in the presence of an asymmetric ligand, (6)
Angew. Chem. Int. Ed. , 37 , 170
3 (1998) and JP-A-8-225466, (7) Angev. Chem. In
t. Ed. 38 , 495 (1999).

[0004]

SUMMARY OF THE INVENTION Among these methods,
The method 1) using an enzyme can obtain alcohols having a relatively high optical purity, but has a problem in that the types of reaction substrates are restricted and the absolute configuration of the obtained alcohols is limited to a specific one. is there.

[0005] Among the methods 2), the method (1) using an asymmetric hydrogenation catalyst for a transition metal has high selectivity for a substrate having a functional group in a molecule such as keto acid. Can produce optically active alcohols, but there is a problem in terms of reaction rate, and it is not an effective method for a relatively simple carbonyl compound having no functional group in the molecule.

The method of (2) using a hydrogen transfer reaction requires a compound serving as a hydrogen source, and the method of (3) has a problem that applicable substrates are limited. The hydrosilylation of (4) is difficult. The cost of the raw material is high, and the method of (5) using borane reduction has a problem in borane handleability.

The method (6) of reacting hydrogen in the presence of a transition metal asymmetric hydrogenation catalyst, an optically active nitrogen-containing compound and a base is an excellent method for producing optically active alcohols. However, since two types of asymmetric sources, an optically active phosphorus ligand and an optically active diamine, which are difficult to obtain, are required, there is a problem that the metal complex catalyst becomes expensive and its preparation becomes complicated.

As described in (7), attempts have been made to improve this disadvantage by using a bidentate phosphorus ligand which is not optically active and has axial asymmetry. Since the synthesis of the phosphorus ligand itself is difficult, and a metal complex catalyst having an unfavorable steric structure is simultaneously formed during the asymmetric reduction reaction, there are problems in optical yield and substrate selectivity.

Therefore, it has been desired to develop a more general and industrially advantageous method for producing an optically active alcohol.

In view of the above circumstances, the present invention provides a practical method for producing optically active alcohols, characterized in that only an optically active amine is used as an asymmetric source and other easily available compounds are used as a catalyst source. The purpose is to do.

[0011]

According to the present invention, there is provided a mixture of a trivalent phosphorus compound having no asymmetric center in the molecule, a transition metal compound and an optically active amine, or a mixture thereof. Formula (1) in the presence of the product

[0012]

Embedded image Ra—CO—Rb (1)

(Wherein Ra and Rb are different from each other, and may be an alkyl group which may have a substituent, an alkenyl group which may have a substituent, and a cycloalkyl which may have a substituent. A carbonyl compound represented by a group, an aralkyl group which may have a substituent or an aryl group which may have a substituent.) And hydrogen. Equation (2)

[0014]

Embedded image Ra—C ^* H (OH) —Rb (2)

(Wherein Ra and Rb have the same meanings as described above, and C ^* represents an asymmetric carbon atom).

In the present invention, preferably, a trivalent phosphorus compound having no asymmetric center in the molecule and a transition metal complex obtained from a transition metal compound and an optically active amine are used in the presence of a predetermined amount of a general formula: (1)

[0017]

Embedded image Ra—CO—Rb (1)

(Where Ra and Rb are different from each other, and may be an alkyl group which may have a substituent, an alkenyl group which may have a substituent, and a cycloalkyl which may have a substituent. A carbonyl compound represented by a group, an aralkyl group which may have a substituent or an aryl group which may have a substituent.) And hydrogen. Equation (2)

[0019]

Embedded image Ra—C ^* H (OH) —Rb (2)

(Wherein Ra and Rb have the same meanings as described above, and C ^* represents an asymmetric carbon atom).

In the present invention, the trivalent phosphorus compound having no asymmetric center in the molecule is preferably represented by the following general formula (3) or (4):

[0022]

Embedded image PR ¹ (R ² ) ₂ (3)

[0023]

Embedded image Ar- (PR ² ₂ ) ₂ (4)

[In the formula, R ¹ and R ² are the same or different and each have an alkyl group which may have a substituent, an alkenyl group which may have a substituent, Each represents a cycloalkyl group, an aralkyl group which may have a substituent, or an aryl group which may have a substituent, and Ar represents an adjacent carbon atom on the aromatic ring,
(PR ² ₂₎ group bonded to an optionally substituted aryl group, or adjacent carbon atoms (PR ² ₂₎ which may have a substituent group is bonded C _2-5 alkylene Represents a group. ] It is a compound represented by these.

The transition metal compound may be selected from the group consisting of
It is preferably a compound of a Group II metal. In this case, the transition metal compound has the following general formula (5)

[0026]

[M _k X _l (L) _m ] _n (5)

(Wherein, M represents a metal of Group VIII of the periodic table or a metal ion thereof, X represents a hydrogen atom, an anion or a zero-valent ligand, and L represents a zero-valent ligand. , K represents an integer of 1 or more, and l, m and n each independently represent 0 or an integer of 1 or more.)

The optically active amine is represented by the following general formula (6)

[0029]

Embedded image R ⁴ C ^* (R ⁵ ) (NR ⁶ R ⁷ ) -R ⁸ C ^* (R ⁹ ) (NR ¹⁰ R ¹¹ ) (6)

(Wherein R ⁴ , R ⁵ , R ⁸ and R ⁹ are each independently a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent A cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent or an aryl group which may have a substituent, and R ⁶ , R ⁷ , R ¹⁰ and R ¹¹ is
Each independently has a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, Represents an optionally substituted aralkyl group or an optionally substituted aryl group, and R ⁴ or R ⁵ and R ⁸ or R ⁹ may combine to form a ring,
⁴ R ⁵ C (NR ⁶ R ⁷ ) may together form a nitrogen-containing heterocycle. C ^* represents an asymmetric carbon atom. Is preferred.

In the present invention, the reaction is carried out in the presence of one or more additives selected from the group consisting of alkali metal salts, alkaline earth metal salts and quaternary ammonium salts in the reaction system. Is preferably performed.

The transition metal complex is preferably represented by the following general formula (7)

[0033]

Embedded image MoXpYq (Px) t ｛R ⁴ R ⁵ C ^* (NR ⁶ R ⁷ ) -R ⁸ R ⁹ C ^* (NR ¹⁰ R ¹¹ )｝ u (7)

(Wherein, M represents a metal of Group VIII of the Periodic Table or a metal ion thereof, X and Y each independently represent a hydrogen atom or an anion, and Px represents an asymmetric center in the molecule. Represents a trivalent phosphorus compound having no, o represents an integer of 1 or more, p, q, t, and u each independently represents an integer of 0 or 1 to 4, and R ^{4 to} R ¹¹ represent The same meaning as described above).

The transition metal complex is more preferably represented by the following general formula (8)

[0036]

Embedded image MX ₂ (Px) ₂ {R ⁴ R ⁵ C ^* (NR ⁶ R ⁷ ) −R ⁸ R ⁹ C ^* (NR ¹⁰ R ¹¹ )} (8)

In the formula, M represents the same meaning as described above, X represents a hydrogen atom or an anion, and Px is a trivalent phosphorus compound having no asymmetric center in the molecule, preferably, a compound represented by the general formula (3) ) or (represents the phosphorus compound represented by 4), R ⁴ ~
R ¹¹ is a compound represented by｝ having the same meaning as described above.

The present invention relates to a product (preferably a product obtained from a trivalent phosphorus compound having no asymmetric center in the molecule, a transition metal compound and an optically active amine) in the carbonyl compound represented by the above general formula (1). Is a method for producing an alcohol represented by the general formula (2), wherein the alcohol is a transition metal complex.

The present invention provides a carbonyl compound represented by the general formula (1) by adding a trivalent phosphorus compound having no asymmetric center in the molecule, a transition metal compound and an optically active amine to a reaction system. By reacting hydrogen, or a product obtained from a trivalent phosphorus compound having no asymmetric center in the molecule, a transition metal compound and an optically active amine is once isolated, and this is used as a catalyst, By reacting hydrogen on the carbonyl compound represented by the general formula (1), the optically active alcohol represented by the general formula (2) is produced.

The present invention provides a trivalent compound having no asymmetric center in a molecule, which is easier to synthesize and obtain, without using an optically active phosphorus compound (optically active phosphorus ligand) which has been difficult to obtain. It is characterized in that a phosphorus compound is used.

According to the present invention, optically active alcohols useful in various uses such as synthetic intermediates of pharmaceuticals and agricultural chemicals and liquid crystal materials can be produced with high selectivity, high yield, and industrial advantage.

[0042]

Next, embodiments of the present invention will be described in detail. The starting compound of the present invention has the following general formula (1)

[0043]

Embedded image Ra—CO—Rb (1)

In the formula (1), Ra and Rb are different from each other, and may be a linear or branched alkyl group which may have a substituent, or a linear or branched alkenyl group which may have a substituent. , A cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent, and an aryl group which may have a substituent.

In the general formula (1), a linear or branched alkyl group which may have a substituent of Ra and Rb, a linear or branched alkenyl group which may have a substituent, As a substituent of a cycloalkyl group which may have a group, an aralkyl group which may have a substituent or an aryl group which may have a substituent, a substituent which does not inhibit this reaction As long as it is a group, there are no particular restrictions on its substitution position, type of substituent, number of substituents, and the like.

As such a substituent, for example, an appropriate substituent selected from a hydrocarbon group, a hydroxy group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an amino group, a heterocyclic group and the like and a halogen atom can be selected.

Examples of the linear or branched alkyl group which may have a substituent include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.
-Butyl, pentyl, isopentyl, neopentyl, t
Examples thereof include alkyl groups having 1 to 20 carbon atoms such as ert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and dodecyl groups.

The linear or branched alkenyl group which may have a substituent includes vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3
-Butenyl, 1,3-butanedienyl and the like having 1 to 1 carbon atoms
20 alkenyl groups can be exemplified.

Examples of the cycloalkyl group which may have a substituent include those having 3 to 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
8 cycloalkyl groups can be exemplified.

Examples of the aralkyl group which may have a substituent include, for example, benzyl, α-methylbenzyl,
Examples thereof include aralkyl groups having 7 to 20 carbon atoms, such as α, α-dimethylbenzyl and α-ethylbenzyl groups.

Examples of the aryl group which may have a substituent include aromatic hydrocarbon groups such as phenyl, naphthyl, anthranyl and phenanthrolyl groups, oxygen-containing aromatic heterocyclic groups such as furyl, pyranyl and benzofuranyl groups; Examples thereof include a sulfur-containing aromatic heterocyclic group such as a thienyl group, a nitrogen-containing heterocyclic group such as xanthenyl, pyrrolyl, pyridyl, imidazolyl, indolyl and carbazoyl groups, and a metallocenyl group such as a ferrocenyl group.

In the method for producing an optically active alcohol of the present invention, the trivalent phosphorus compound (Px) having no asymmetric center in the molecule may be represented by the general formula (3) or (4):

[0053]

Embedded image PR ¹ (R ² ) ₂ (3)

[0054]

Embedded image Ar- (PR ² ₂ ) ₂ (4)

The compound represented by the following formula (1) can be preferably used. In the above formulas (3) and (4), R ¹ and R ² are the same or different and each represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. Represents an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group, and Ar represents ( PR ² ₂₎ group is an aryl group which may have a substituent bonded, or may have a substituent group,
It represents ethylene, propylene, a C _2-5 alkylene group such as butylene.

In the general formula (3) or (4), R
^1, R ² which may have a substituent a straight or branched alkyl group which may have a substituent straight or branched alkenyl group, cycloalkyl which may have a substituent As the substituent of the group, the aralkyl group which may have a substituent or the aryl group which may have a substituent, as long as it is a substituent which does not inhibit the present reaction, its substitution position, substitution There are no particular restrictions on the type of group, the number of substituents, and the like.

As such a substituent, for example, a hydrocarbon group, a hydroxy group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an amino group, a heterocyclic group and the like, and an appropriate one from a halogen atom can be used.

Examples of the linear or branched alkyl group which may have a substituent include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert.
-Butyl, pentyl, isopentyl, neopentyl, t
Examples thereof include an alkyl group having 1 to 20 carbon atoms such as ert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl and the like.

Examples of the alkenyl group which may have a substituent include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
An alkenyl group having 1 to 20 carbon atoms such as a 3-butanedienyl group can be exemplified.

Examples of the optionally substituted cycloalkyl group include those having 3 to 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
8 cycloalkyl groups and the like.

Examples of the aralkyl group which may have a substituent include, for example, benzyl, α-methylbenzyl,
Examples thereof include aralkyl groups having 7 to 20 carbon atoms, such as α, α-dimethylbenzyl and α-ethylbenzyl groups.

Examples of the aryl group which may have a substituent include aromatic hydrocarbon groups such as phenyl, naphthyl, anthranyl and phenanthrolyl groups, oxygen-containing aromatic heterocyclic groups such as furyl, pyranyl and benzofuranyl groups; Examples thereof include a sulfur-containing aromatic heterocyclic group such as a thienyl group, a nitrogen heterocyclic group such as xanthenyl, pyrrolyl, pyridyl, imidazolyl, indolyl, and carbazoyl; and a metallocenyl group such as a ferrocenyl group.

Examples of such phosphorus compounds include trimethylphosphine, triethylphosphine, triisopropylphosphine, ethyldiisopropylphosphine,
Trialkylphosphines such as methyldiphenylphosphine, dialkylarylphosphines such as dimethylphenylphosphine, triarylphosphines such as triphenylphosphine and tri (3,5-xylyl) phosphine, and triphenylphosphine. Monodentate phosphines such as phosphites such as phyt;

Bidentate phosphines such as 1,2-bis (diphenylphosphino) ethane, 1,2-bis (diphenylphosphino) benzene, and 1,2-diphosphoranobenzene are exemplified. it can.

The transition metal compound is represented by the following general formula (5)

[0066]

Embedded image [M _k X _l (L) _m ] _n (5)

The compounds represented by the following formulas are preferred. Where M
Represents a metal of Group VIII of the periodic table such as Ru, Rh, Ir, Pt or a metal ion, and among them, it is particularly preferable that M is Ru or a Ru ion.

X represents an anion such as a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group or an alkoxyl group, or a ligand such as benzene, cyclooctadiene (COD), cyclooctatriene (COT) or carbon monoxide.

L represents a zero-valent ligand such as water, benzene, COD, COT, and carbon monoxide. k represents an integer of 1 or more, and l, m, and n each independently represent an integer of 0 or more.

As the transition metal compound, for example, R
metal salts such as uCl ₃ .3H ₂ O, Ru (1,5-CO
D) (1,3,5-COT), (RuCl ₂ (C
_{6 H 6)) 2, RuCl} 2 (1,5-COD) a transition metal complex or the like can be exemplified.

The optically active amine is represented by the general formula (6)

[0072]

Embedded image R ⁴ R ⁵ C ^* (NR ⁶ R ⁷ ) —R ⁸ R ⁹ C ^* (NR ¹⁰ R ¹¹ ) (6)

The compounds represented by the following formulas are preferred. Equation (6)
Wherein R ⁴ , R ⁵ , R ⁸ and R ⁹ are each independently
A hydrogen atom, a linear or branched alkyl group which may have a substituent, a linear or branched alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, It represents an aralkyl group which may have a substituent or an aryl group which may have a substituent. Also,
R ⁶ , R ⁷ , R ¹⁰ and R ¹¹ are each independently a hydrogen atom, a linear or branched alkyl group which may have a substituent, a linear group which may have a substituent or It represents a branched alkenyl group, a cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent or an aryl group which may have a substituent.

Further, one of R ⁴ and R ⁵ and R ¹⁰ and R
Any one of ¹¹ may form a ring with a carbon chain, or R ⁴ R ⁵ C ^* (NR ⁶ R ⁷ ) may have a substituent It may form a nitrogen heterocycle (wherein C ^* represents an asymmetric carbon).

In the above formula (6), a linear or branched alkyl group which may have a substituent of R ^{4 to} R ^11, a linear or branched alkenyl group which may have a substituent As a substituent of a cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent or an aryl group which may have a substituent, If there are no substituents, there are no particular restrictions on the substitution position, the type of substituent, the number of substituents, and the like.

Such a substituent may be, for example, a hydrocarbon group, a hydroxy group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an amino group, a heterocyclic group, and the like, and an appropriate substituent.

Examples of the linear or branched alkyl group which may have a substituent include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert.
-Butyl, pentyl, isopentyl, neopentyl, t
Examples thereof include alkyl groups having 1 to 20 carbon atoms such as ert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and dodecyl groups.

Examples of the alkenyl group which may have a substituent include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
An alkenyl group having 1 to 20 carbon atoms such as a 3-butanedienyl group can be exemplified.

Examples of the cycloalkyl group which may have a substituent include those having 3 to 3 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
8 cycloalkyl groups can be exemplified.

Examples of the aralkyl group which may have a substituent include, for example, benzyl, α-methylbenzyl,
Examples thereof include aralkyl groups having 7 to 20 carbon atoms, such as α, α-dimethylbenzyl and α-ethylbenzyl groups.

Examples of the aryl group which may have a substituent include aromatic hydrocarbon groups such as phenyl, naphthyl, anthranyl and phenanthrolyl groups, oxygen-containing aromatic heterocyclic groups such as furanyl, pyranyl and benzofuranyl groups; Examples thereof include a sulfur-containing aromatic heterocyclic group such as a thienyl group, a nitrogen-containing heterocyclic group such as xanthenyl, pyrrolyl, pyridyl, imidazolyl, indolyl, and carbazoyl groups, and a metallocenyl group such as a ferrocenyl group.

Examples of such diamines include optically active 1,2-diphenylethylenediamine, 2,3-diaminobutane, 1-methyl-2,2-diphenylethylenediamine, 4-methyl-1,2-diamino-1, 1-diphenylpentane, 3-methyl-1,2-diamino-1,
1-diphenylbutane, 1,2-diamino-1,1-di (p-methoxyphenyl) propane, 4-methyl-1,
2-diamino-1,1-di (p-methoxyphenyl) pentane, 3-methyl-1,2-diamino-1,1-di (p-methoxyphenyl) butane, 1,2-diamino-
1,1-di (p-methoxyphenyl) -3-phenylpropane, 1,2-diamino-1,1-dinaphthylpropane, 4-methyl-1,2-diamino-1,1-dinaphthylpentane and the like Examples can be given.

When any of R ⁴ and R ⁶ and any one of R ¹⁰ and R ¹¹ together form a ring with a carbon chain, examples thereof include optically active 1,2-diaminocyclopentane,
Examples thereof include 2-diaminocyclohexane and 1,2-diaminocycloheptane.

Examples of the case where R ⁴ R ⁵ C ^* (NR ⁶ R ⁷ ) together form a nitrogen-containing heterocyclic ring which may have a substituent include 2- (aminomethyl) pyrrolidine, 2- (1-aminoethyl) pyridine and the like can be exemplified.

As the additive, an alkali metal salt or an alkaline earth metal salt is preferable. As such an additive, for example, general formula (9)

[0086]

Embedded image MbZ (9)

The following can be exemplified.
In the formula (9), Mb represents a metal such as an alkali metal and an alkaline earth metal, and Z represents a group such as a hydroxyl group, an alkoxyl group, and a mercapto group.

As such an additive, more specifically, K
OH, KOCH_Three, KOCH (CH _Three)_Two, KC_TenH₈,
NaOH, NaOCH_Three, LiOH, LiOCH_Three, L
iOCH (CH_Three)_Two, Mg (OC_TwoH_Five)_Two, NaSH
And the like.

Also, quaternary such as tetramethylammonium chloride, tetramethylammonium bromide, hydroxytetramethylammonium, tetraethylammonium chloride, tetraethylammonium bromide, hydroxytetraethylammonium, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide and hydroxybenzyltrimethylammonium Ammonium salts can be used as well.

In the present invention, a trivalent phosphorus compound having no asymmetric center in the molecule (ligand) may be added to the carbonyl compound represented by the general formula (1) in the presence or absence of an additive. ), A predetermined amount (catalytic amount) of a product derived from a transition metal compound and an optically active amine, and reacting with hydrogen or a compound that donates hydrogen.

In order to actually perform this reduction reaction,
A trivalent phosphorus compound having no asymmetric center in the molecule, a transition metal compound and an optically active amine are added to the reaction system, and the product is represented by the general formula (1) without isolation. By reacting a carbonyl compound with hydrogen, or once isolating a product obtained from a trivalent phosphorus compound having no asymmetric center in the molecule, a transition metal compound and an optically active amine, using this as a catalyst By reacting hydrogen on the carbonyl compound represented by the general formula (1).

The order of addition of the carbonyl compound represented by the general formula (1), the trivalent phosphorus compound having no asymmetric center in the molecule, the transition metal compound and the optically active amine to the reaction system is, in particular, It doesn't matter. The reaction can be appropriately carried out in the most preferable mode depending on the type of the reaction substrate, the type of the catalyst, the type of the solvent used, and the like.

The amount of the trivalent phosphorus compound (ligand) having no asymmetric center in the molecule, the transition metal compound and the product derived from the optically active amine varies depending on the reaction vessel and economic efficiency. , A molar ratio of 1/100 to 1 / 1,000, based on the carbonyl compound (1) as a reaction substrate.
000, preferably 1/1000
１ ／ 1 / 100,000.

When the above-mentioned additives are used, the amount of the additives used is 0.5 to 100 equivalents, preferably 2 to 40 equivalents to the above-mentioned product, but it may be changed appropriately. Can be.

This reaction is usually performed in an inert solvent. As such a solvent, any inert solvent can be used without particular limitation, but the reaction raw material, the product,
Those that substantially solubilize the additive are preferred.

Solvents that can be used in the reaction include
More specifically, aromatic solvents such as toluene and xylene, aliphatic solvents such as pentane and hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ether solvents such as ether and tetrahydrofuran, methanol, ethanol, and 2-propanol , Butanol, alcohol solvents such as benzyl alcohol, and acetonitrile, D
An organic solvent containing a hetero atom such as MF (N, N-dimethylformamide), N-methylpyrrolidone, pyridine, and DMSO (dimethylsulfoxide) can be used.

In the present invention, among these, alcohol-based solvents are particularly preferred because the product is alcohol. These solvents can be used alone, but a mixed solvent of two or more of these can also be used.

The amount of the solvent used is determined by the solubility and economical efficiency of the reaction substrate.
-In the case of propanol, the concentration of the substrate can be as low as 1% or less, and can be carried out in a solvent-free state.
It is preferred to use it in% by weight.

Examples of the hydrogen source used for the hydrogen reduction reaction include a hydrogen storage alloy in addition to hydrogen gas. The pressure of hydrogen is usually in the range of 1 to 200 atm, and 3 to 1 atm.
A range of 00 atm is more preferred.

The reaction temperature is -30 ° C. in consideration of economy.
To 100 ° C., but the present invention
At around room temperature of 室温 40 ° C., the reaction proceeds smoothly. Also,
The reaction time varies depending on the reaction conditions such as the concentration of the reaction substrate, temperature, and pressure, but the reaction is usually completed in a few minutes to 30 hours.

The present invention can be carried out in a batch mode or a continuous mode.

When the above-mentioned product, that is, a transition metal complex which is a catalyst for asymmetric reduction reaction is isolated and used, a trivalent phosphorus compound having no asymmetric center in the molecule, a transition metal compound and an optically active amine are used. There is no particular limitation as long as it is a preparation / isolation method that can be prepared and gives a product having a catalytic ability for this reaction.

The method for preparing such a catalyst includes the following A)
To D). A) For example, Experimental Chemistry, Vol. 18, p. 261 (Maruzen)
A trivalent phosphorus compound having no asymmetric center in the molecule represented by the general formula PR ¹ (R ² ) ₂ (3),
General formula MX ₂ (PR ¹⁾ obtained by reacting with a transition metal compound represented by the general formula [M _k X _l (L) _m ] _n (5)
The compound represented by (R ² ) ₂ ) ₂ (10) is isolated.

Next, for example, Fineke
Mikarus. ,28, P60 (1999).
And the general formula R^FourR^FiveC^*(NR⁶R⁷) -R⁸R⁹C^*
(NR ^TenR¹¹) The optically active diamine represented by (6)
In response, the general formula MX_Two(Px)_Two｛R^FourR^FiveC^:(N
R⁶R⁷) -R⁸R⁹C^:(NR^TenR¹¹)｝ (8)
The product obtained is isolated. This product is used as a catalyst precursor.
(Hereinafter, this method is referred to as "method A").
U).

B) Formula MX ₂ (PR ¹ (R ² ) ₂ )
₂ A compound represented by the general formula R ⁴ R ⁵ C
^{* (NR 6 R 7) -R} 8 R 9 C * (NR 10 R 11) (6)
And an optically active diamine represented by, for example, Fine Chemicals. , Vol. 28, p60 (1999), and using the reacted reaction solution as it is as a catalyst precursor solution (hereinafter, this method is referred to as "method B").

C) For example, Experimental Chemistry Course, Vol. 18, p2
According to the method of 61 (Maruzen), the general formula PR ¹ (R ² ) ₂
Reacting a trivalent phosphorus compound having no asymmetric center in the molecule represented by (3) with a transition metal compound represented by the general formula [M _k X _l (L) _m ] _n (5) A reaction solution of the compound represented by the general formula (10) obtained by the above method is added to, for example, Fine Chemicals. , 28, according to the method of 60 (1999), the general formula ^{R 4 R 5 C * (NR} 6 R 7) -R 8 R 9 C
^{* A} method in which a reaction solution obtained by reacting the optically active diamine represented by (NR ¹⁰ R ¹¹ ) (6) is used as it is as a catalyst precursor solution (hereinafter, this method is referred to as “method C”).

D) For example, fine chemicals. ,2
8, P61 (1999).
^Two _Two)_TwoThree that have no asymmetric center in the molecule represented by (4)
A phosphorus compound of the general formula [M_kX_l(L)_m]
_nObtained by reacting with the transition metal compound represented by (5).
General formula MX_Two[(Ar)-(PR^Two _Two)_Two] (So
lvent)_wA compound represented by the general formula R
^FourR^FiveC^*(NR⁶R⁷) -R ⁸R⁹C^*(NR
^TenR¹¹) Reacting the optically active diamine represented by (6)
Formula MX obtained by_Two(Px)_Two｛R^FourR^FiveC^*(N
R⁶R⁷) -R⁸R⁹C^*(NR^TenR¹¹)｝ (8)
The product to be used is isolated, and this product is used as a catalyst precursor.
Method used (hereinafter, this method is referred to as “method D”).

The structure of the compound represented by the general formula (8) is represented by NMR, IR, elemental analysis, absorption spectrum (visible,
UV), optical rotation measurement, X-ray crystallography and the like.

Representative examples of the compound represented by the general formula (8) obtained as described above are shown in Tables 1 and 2 below. In Tables 1 and 2 below, each symbol has the following meaning. (S, s) -DPEN: (s, s) -diphenylethylenediamine (1s, 2s) -CHDN: 1,2-cyclohexanediamine (s) -DAIPEN: 1-isopropyl-2,2-
(P-dimethoxyphenyl) ethylenediamine cPr: cyclopropyl cPen: cyclopentyl cHex: cyclohexyl cHep: cycloheptyl

[0110]

[Table 101]

[0111]

[Table 102]

[0112]

[Table 103]

[0113]

[Table 104]

[0114]

[Table 105]

[0115]

[Table 106]

[0116]

[Table 107]

[0117]

[Table 108]

[0118]

[Table 201]

[0119]

[Table 202]

[0120]

[Table 203]

[0121]

[Table 204]

[0122]

[Table 205]

[0123]

[Table 206]

[0124]

[Table 207]

[0125]

[Table 208]

[0126]

[Table 209]

[0127]

[Table 210]

[0128]

Next, the present invention will be described in more detail by way of examples. In the following, each unit operation was performed under an argon gas flow. The physical property data was measured with the following measuring instruments and conditions.

(High Performance Liquid Chromatography) Equipment: Shimadzu LC-10A Column: Daicel CHIRALPAKOB Solvent: n-hexane / 2-propanol (10/1)

Example 1 Synthesis of Optically Active 1-Phenylethanol by Method A Ruthenium Chloride Trihydrate (1.0 g; 3.8 mmol)
1) was dissolved in methanol (200 ml), refluxed for 5 minutes, and after cooling, tris- (3,5-xylyl) phosphine (7.94 g; 22.9 mmol) was added to give a further 4
Refluxed for hours. After cooling the reaction solution, methanol was distilled off (180 ml), and the precipitated crystals were collected by filtration, washed twice with degassed ether (10 ml), and dried under reduced pressure.

One half of the obtained crystal (4.6 g) was dissolved in toluene (20 ml), and (1S, 2
S) -1,2-diphenylethylenediamine (610 m
g; 2.86 mmol, hereinafter, “(s, s) DPEN”
) Was added dropwise over 30 minutes. After stirring at room temperature for a further 18 hours, the solvent was replaced with methylene chloride (20 ml). The insoluble crystals precipitated at this time were separated by filtration, and the methylene chloride mother liquor of the filtrate was concentrated until crystals precipitated. To this solution was added degassed ether (10 m
l) was added and the crystals were filtered off.

The obtained crystals were separated from degassed ether (5 m
After washing twice in l) and drying under reduced pressure, ΔRuC
l ₂ [(3,5-xylyl) ₃ P] ₂ (s, s) DP
1.31 g of crystals of EN｝ (Compound No. I-29)
(1.2 mmol, 63% yield). Its deduced structural formula and ³¹ P-NMR and ¹ H-NMR data are shown below.

[0133]

Embedded image

³¹ P-NMR (δ ppm): 44.61 p
pm ¹ H-NMR (δ ppm, TMS): 2.05 (s, 1
2H), 3.78 (m, 2H), 4.25 (m, 2
H), 4.65 (m, 2H), 6.7-8.0 (m, 1
6H)

Next, 8 ml of isopropanol was placed in a 100 ml pressure-resistant reaction vessel, and ｛RuCl ₂ [(3,5
Dissolve 5.4 mg (0.0050 mmol) of crystals of -xylyl) ₃ P] ₂ (s, s) DPEN} and acetophenone (6.44 g; 53.6 mmol), and further add a solution of t-BuOK in 2-propanol ( (0.5N solution, 0.5 ml). 1 hydrogen in the reaction vessel
After pressurizing to 1 atm, sealing and stirring at room temperature for 18 hours, hydrogen was pressurized to 11 atm again, and stirring of the reaction mixture was continued to complete the reaction. The reaction product was concentrated and the resulting crude product was purified by silica gel chromatography (eluent: ether) to obtain optically active (R) -1-phenylethanol (6.57 g; yield 100%). The optical purity of the obtained (R) -1-phenylethanol is 8
It was 7% ee.

Example 2 Synthesis of Optically Active 1-Phenylethanol by Method C Ruthenium Chloride Trihydrate (1.80 mg; 0.006)
9 mmol) and tris- (3,5-xylyl) phosphine (14.4 mg; 0.042 mmol) were dissolved in methanol (5 ml) and refluxed for 3 hours. After cooling, methanol was distilled off under reduced pressure, and the precipitated crystals were collected by filtration. The obtained crystals and (s, s) DPEN (1.90 mg; 0.0088)
mmol) was placed in a 100 ml pressure vessel and dissolved in toluene (2 ml). After stirring this solution at room temperature for 3 hours, the solvent was dissolved in 2-propanol (5 ml) and refluxed for another 3 hours.

Next, the (s, s) DPEN (1.90 m
g: 0.008 mmol) This solution was added to a pressure-resistant reaction vessel previously charged with 100 ml, and stirred at room temperature for 3 hours.
Acetophenone (6.54 g, 4 m
mol) and 0.5N t-BuOK in 2-propanol (0.5 ml) were further added, and hydrogen was injected into the reaction vessel to 11 atm, sealed, stirred at room temperature for 18 hours, and hydrogenated again. Was pressurized to 11 atm, and stirring was continued to complete the reaction. The crude product obtained by concentrating the reaction solution was purified by silica gel chromatography (eluent; ether) to obtain optically active (R) -1-phenylethanol (6.55 g; 99% yield). . The optical purity of the obtained optically active (R) -1-phenylethanol was 87% ee.

[0138]

As described above, according to the present invention,
The product obtained from an easily available trivalent phosphorus compound having no asymmetric center in the molecule, a transition metal compound, and an optically active amine is used as an asymmetric hydrogen reduction catalyst. Optically active alcohols useful in various applications of can be produced with high selectivity, high yield, and industrially advantageous.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07F 15/00 C07F 15/00 A // C07B 61/00 300 C07B 61/00 300 C07M 7:00 F term (Ref.) BC11 BN10 FE11 4H039 CA60 CB20 4H050 AB81 AC40 BA17 BA34 WB14 WB16

Claims (10)

[Claims] 1. A compound of the general formula (1) in the presence of a mixture of a trivalent phosphorus compound having no asymmetric center in the molecule, a transition metal compound and an optically active amine or a product obtained therefrom. Ra-CO-Rb (1) (wherein Ra and Rb are different from each other and have an alkyl group which may have a substituent, an alkenyl group which may have a substituent, Represents an optionally substituted cycloalkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group.) And hydrogen. Wherein Ra—C ^* H (OH) —Rb (2) wherein Ra and Rb have the same meanings as described above, and C ^* represents an asymmetric carbon atom. The method for producing an optically active alcohol represented by: 2. In the presence of a predetermined amount of a trivalent phosphorus compound having no asymmetric center in the molecule and a transition metal complex obtained from a transition metal compound and an optically active amine, a compound represented by the general formula (1): Ra-CO-Rb (1) (wherein, Ra and Rb are different from each other and each have an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. A cycloalkyl group, an aralkyl group which may have a substituent or an aryl group which may have a substituent, respectively) and hydrogen. Characteristic, general formula (2): Ra-C ^* H (OH) -Rb (2) (where Ra and Rb have the same meanings as described above, and C ^* represents an asymmetric carbon atom. )), A method for producing an optically active alcohol. 3. The trivalent phosphorus compound having no asymmetric center in the molecule is represented by the following general formula (3) or (4): PR ¹ (R ² ) ₂ (3) Ar- (PR ² ₂ ) ₂ (4) wherein R ¹ and R ² are the same or different and each may be an alkyl group which may have a substituent, or an alkenyl which may have a substituent. A group, a cycloalkyl group optionally having substituent (s), an aralkyl group optionally having substituent (s) or an aryl group optionally having substituent (s), Ar
Is the adjacent carbon atoms on the aromatic ring, (PR ² ₂ group) which may have a substituent attached an aryl group, or adjacent (PR ² ₂₎ to a carbon atom substituent group is bonded Represents a C _2-5 alkylene group which may have The method for producing an optically active alcohol according to claim 1 or 2, wherein the compound is a compound represented by the formula: 4. The method for producing an optically active alcohol according to claim 1, wherein the transition metal compound is a compound of a Group VIII metal of the periodic table. 5. The transition metal compound represented by the general formula (5): [M _k X _l (L) _m ] _n (5) wherein M is a metal of Group VIII of the periodic table or the metal X represents a hydrogen atom, an anion or a zero-valent ligand, L represents a zero-valent ligand, k represents an integer of 1 or more, and l, m, and n are each independently Represents a compound represented by 0 or an integer of 1 or more).
The method for producing an optically active alcohol according to the above. 6. The optically active amine is represented by the general formula (6): R ⁴ C ^* (R ⁵ ) (NR ⁶ R ⁷ ) -R ⁸ C ^* (R ⁹ ) (NR ¹⁰ R ¹¹ ) ( 6) (wherein, R ⁴ , R ⁵ , R ⁸ and R ⁹ are each independently a hydrogen atom, an alkyl group which may have a substituent,
Represents an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent or an aryl group which may have a substituent. , R ⁶ , R ⁷ , R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. Represents an optionally substituted cycloalkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group, wherein R ⁴ or R ⁵ is bonded to R ⁸ or R ⁹ To form a ring, or R ⁴ R ⁵ C (N
R ⁶ R ⁷ ) may together form a nitrogen-containing heterocycle. C ^* represents an asymmetric carbon atom. )
The method for producing an optically active alcohol according to claim 1 or 2, which is a compound represented by the formula: 7. The reaction according to claim 1, wherein the reaction is carried out in the presence of one or more additives selected from the group consisting of alkali metal salts, alkaline earth metal salts and quaternary ammonium salts. The method for producing the optically active alcohol described in the above. 8. The transition metal complex is represented by the following general formula (7): MoXpYq (Px) t ｛R^FourR^FiveC^*(NR⁶R⁷) -R⁸R⁹C^*(NR ^Ten R¹¹)｝ U (7) (wherein M is a metal of Group VIII of the periodic table or a metal ion thereof)
X and Y each independently represent a hydrogen atom or
Represents a nonion, and Px represents a group having no asymmetric center in the molecule.
Represents a monovalent phosphorus compound, o represents an integer of 1 or more,
p, q, t, and u are each independently 0 or 1 to 4;
Represents an integer, R^Four~ R¹¹Has the same meaning as described above. )so
The optically active alcohol according to claim 2, which is a compound represented by the formula:
Manufacturing method of the tool. 9. The transition metal complex represented by the following general formula (8): MX ₂ (Px) ₂ ｛R ⁴ R ⁵ C ^* (NR ⁶ R ⁷ ) -R ⁸ R ⁹ C ^* (NR ¹⁰ R ¹¹ )} (8) In the formula, M represents the same meaning as described above, X represents a hydrogen atom or an anion, and Px represents 3 having no asymmetric center in the molecule.
The method for producing an optically active alcohol according to claim 2, wherein the compound represents a phosphorus compound having a valency, and R ^{4 to} R ¹¹ are compounds represented by｝ having the same meaning as described above. 10. A formula (8): MX ₂ (Px) ₂ {R ⁴ R ⁵ C ^* (NR ⁶ R ⁷ ) −R ⁸ R ⁹ C ^* (NR ¹⁰ R ¹¹ )} (8) In the formula, M represents the same meaning as described above, X represents a hydrogen atom or an anion, and Px represents 3 having no asymmetric center in the molecule.
A compound represented by｝, which represents a monovalent phosphorus compound and R ^{4 to} R ¹¹ have the same meaning as described above.