JP4482299B2 - Ruthenium compound and method for producing optically active alcohol compound - Google Patents

Description

  The present invention relates to a novel ruthenium compound useful as an asymmetric hydrogenation catalyst for a carbonyl compound, and a method for producing an optically active alcohol compound in which the carbonyl compound is asymmetrically hydrogenated using the ruthenium compound as an asymmetric hydrogenation catalyst.

  Conventionally, as a method for producing an optically active alcohol compound, a method of catalytically asymmetrically hydrogenating a carbonyl compound such as a ketone is known. For example, a method using a rhodium complex described in Non-Patent Documents 1 and 2, a method using an iridium complex described in Non-Patent Document 3, a method by hydrogen transfer using ruthenium as a catalyst described in Patent Document 1, a patent A hydrogenation method using ruthenium described in Document 2 as a catalyst is known.

However, among these methods, the methods described in Non-Patent Documents 1 to 3 are so-called noble metals such as rhodium and iridium, which are relatively expensive metals, and have a low hydrogenation activity and asymmetric hydrogenation. When used as a catalyst, a relatively high temperature or a high hydrogen pressure is required. The method described in Patent Document 1 must use an organic compound such as formic acid as a hydrogen source, which is disadvantageous in terms of operation and cost as compared to using an inexpensive hydrogen source such as hydrogen gas. In addition, the method described in Patent Document 2 is an excellent method for asymmetric hydrogenation of carbonyl compounds, but an expensive bidentate phosphine ligand having a plurality of substituents and a diamine coordination that is difficult to synthesize. There is a problem that good results cannot be obtained unless a catalyst having a child is used.
Therefore, development of an inexpensive asymmetric hydrogenation catalyst capable of producing a corresponding optically active alcohol compound from a carbonyl compound with high selectivity and high yield using an inexpensive hydrogen source such as hydrogen gas has been desired.

Chemistry Letters, 1982 p. 261 Tetrahedron Letters, 1994 Vol. 35 p. 4963 Journal of American Chemical Society, 1993, Vol. 115, p. 3318 Japanese Patent Laid-Open No. 10-130289 JP 11-189600 A

  The present invention has been made in view of such a situation, is easily available, and is useful as a catalyst for asymmetric hydrogenation of carbonyl compounds, and an optically active alcohol using this ruthenium compound as an asymmetric hydrogenation catalyst It is an object to provide a method for producing a compound.

  In order to solve the above problems, the present invention firstly provides a compound of formula (I)

[Wherein, X and Y each independently represent a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group or a C1-C20 alkoxy group.
Px represents a phosphine ligand, and n represents 1 or 2.
A represents a diamine ligand represented by the following formula (1) .

[In the formula, R ¹ is (halogen atom, C3-C8 cycloalkyl group, C1-C20 alkoxy group, phenyl group, 1-naphthyl group, 2-naphthyl group, acetyl group, propionyl group, isopropionylcarbonyl group, benzoyl Group, a phenylmethylcarbonyl group, a C1-C12 alkylcarbonyloxy group, an oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, or a nitrogen-containing heterocyclic group),
(Halogen atom, C1-C20 alkyl group, C2-C20 alkenyl group, C3-C8 cycloalkyl group, C1-C20 alkoxy group, acetyl group, propionyl group, isopropionylcarbonyl group, benzoyl group, phenylmethylcarbonyl group, C1- A C7-C20 aralkyl group optionally substituted with a C12 alkylcarbonyloxy group, an oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, or a nitrogen-containing heterocyclic group, or
(Halogen atom, C1-C20 alkyl group, C2-C20 alkenyl group, C3-C8 cycloalkyl group, C7-C20 aralkyl group, C1-C20 alkoxy group, C7-C20 aralkyl group, phenyl group, 1-naphthyl group, 2 -Naphthyl group, acetyl group, propionyl group, isopropionylcarbonyl group, benzoyl group, phenylmethylcarbonyl group, C1-C12 alkylcarbonyloxy group, oxygen-containing heterocyclic group, sulfur-containing heterocyclic group, or nitrogen-containing heterocyclic group) Represents an optionally substituted phenyl group,
R ² and R ³ represent a methyl group. R ² and R ³ may be bonded together to form a ring. ]
The ruthenium compound represented by these is provided.

In the ruthenium compound of the present invention, the compound in which Px is an optically active phosphine ligand is preferable, and the compound in which A is an optically active diamine ligand is preferable.
The ruthenium compound of the present invention is preferably such that A is a diamine ligand of a phenyl group that R ¹ may have a substituent in the formula (1) or (2), and R ² and R ^{What 3} is a diamine ligand of a methyl group is preferable.

The present invention secondly provides an asymmetric hydrogenation catalyst comprising the ruthenium compound of the present invention.
Thirdly, the present invention provides a method for producing an optically active alcohol compound, characterized in that a carbonyl compound is hydrogenated in the presence of the ruthenium compound of the present invention.

  According to the present invention, a new ruthenium compound useful as an asymmetric hydrogenation catalyst for a carbonyl compound, which is easily available and inexpensive, is provided. Further, according to the present invention, a corresponding optically active alcohol compound can be produced from a carbonyl compound with high selectivity and high yield using an inexpensive hydrogen source such as hydrogen gas in the presence of the ruthenium compound. .

  Hereinafter, the present invention will be described in detail by dividing it into 1) a ruthenium compound and an asymmetric hydrogenation catalyst, and 2) a method for producing an optically active alcohol.

1) Ruthenium compound and asymmetric hydrogenation catalyst The first of the present invention is a ruthenium compound represented by the following formula (I).

  In the formula (I), X and Y are each independently a hydrogen atom; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a carboxyl group; a hydroxyl group; or a methoxy group, an ethoxy group, a propoxy group, Represents a C1-C20 alkoxy group such as an isopropoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, a cyclohexyloxy group, or a dodecyloxy group;

(1) Phosphine ligand (Px)
Px represents a phosphine ligand. Px is not particularly limited as long as it can stably form a ruthenium compound. From the viewpoint of obtaining a ruthenium compound having excellent asymmetric hydrogenation catalytic activity, an optically active phosphine ligand. Is preferred.

  As said Px, the monodentate phosphine ligand represented by Formula (3) shown below and the bidentate phosphine ligand represented by Formula (4) can be illustrated.

In the monodentate phosphine ligand represented by the formula (3), R _A , R _B and R _C are each independently methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec -C1-C20 alkyl group such as butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, heptyl group, nonyl group, dodecyl group; phenyl group which may have a substituent; cyclopropyl group, cyclopentyl A C3-C8 cycloalkyl group such as a group, a cyclohexyl group or a cyclooctyl group; a C7-C20 aralkyl group such as a benzyl group, an α-methylbenzyl group or an α, α-dimethylbenzyl group; Also, two of R _A , R _B and R _C may be bonded to form a heterocycle containing P which may have a substituent.

  Examples of the substituent of the heterocyclic ring containing phenyl group and P include, for example, halogen atom such as fluorine atom, chlorine atom, bromine atom; hydroxyl group; methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, C1-C20 alkyl groups such as heptyl group, nonyl group, dodecyl group; C2-C20 alkenyl groups such as vinyl group, propenyl group, butenyl group, 2-hexenyl group; C3-C3 such as cyclopropyl group, cyclobutyl group, cyclopentyl group, etc. C8 cycloalkyl group; C7-C20 aralkyl group such as benzyl group, α-methylbenzyl group, α, α-dimethylbenzyl group; aryl group such as phenyl group, 1-naphthyl group, 2-naphthyl group; methoxy group, ethoxy Group, n-propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, dodecyloxy group C1~C20 alkoxy group such as a group; acetoxy group, propionyloxy group, an acyloxy group such as a benzoyloxy group; dioxolan-2-yl, the heterocyclic group such as oxazolin-2-yl; and the like.

Specific examples of the monodentate phosphine ligand represented by the formula (3) include trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, tricyclohexylphosphine, tri (p-tolyl) phosphine, diphenylmethylphosphine, dimethyl Tertiary phosphines such as phenylphosphine, diisopropylmethylphosphine, 1- [2- (diphenylphosphino) ferrocenyl] ethyl methyl ether, 2- (diphenylphosphino) -2′-methoxy-1,1′-binaphthyl are suitable. Can be cited as a thing. In addition, a phosphine ligand having a substituent in which R _A , R _B and R _C are different from each other, such as ethylmethylbutylphosphine, ethylmethylphenylphosphine, isopropylethylmethylphosphine, and cyclohexyl (O-anisyl) methylphosphine, is used. You can also.

In the bidentate phosphine ligand represented by the formula (4), R _D , R _E , R _F and R _G are each independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n -Butyl group, sec-butyl group, t-butyl group, pentyl group and its isomer, hexyl group and its isomer, heptyl group and its isomer, nonyl group and its isomer, dodecyl group and its isomer, etc. A C1-C20 alkyl group; a phenyl group which may have a substituent; or a C3-C8 cycloalkyl group such as a cyclopropyl group, a cyclopentyl group or a cyclohexyl group; In addition, _RD and R _E and / or R _F and _RG may combine to form a heterocyclic ring containing P which may have a substituent.

  Examples of the substituent for the phenyl group and heterocyclic ring include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; hydroxyl group; C1-C20 alkyl group such as methyl group, ethyl group, propyl group and butyl group; vinyl Groups, propenyl groups, butenyl groups, etc., C2-C20 alkenyl groups; cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, etc., C3-C8 cycloalkyl groups; benzyl groups, α-methylbenzyl groups, α, α-dimethylbenzyl groups, etc. An aryl group such as a phenyl group, a 1-naphthyl group and a 2-naphthyl group; a C1 to C20 alkoxy group such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group and a butoxy group; Groups, propionyloxy groups, acyloxy groups such as benzoyloxy groups; dioxolan-2-yl , Heterocyclic group such as oxazolin-2-yl group; and the like.

  W may have a C1-C5 alkylene group which may have a substituent, a C3-C6 cycloalkylene group which may have a substituent, an arylene group which may have a substituent, or a substituent. The C2-C20 alkene diyl group which may be good, or the C2-C20 alkyne diyl group which may have a substituent is represented.

Examples of the C1-C5 alkylene group include a methylene group, an ethylene group, and a propylene group.
Examples of the C3-C6 cycloalkylene group include a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, and a cyclohexylene group.
Examples of the arylene group include phenylene group, naphthylene group, 1,1′-biphenyl-2,2′-diyl group, 1,1′-binaphthyl-2,2′-diyl group, 1,1′-binaphthyl-7, 7'-diyl group etc. are mentioned.
Examples of the C2-C20 alkenediyl group include an ethenediyl group, a propenediyl group, an isopropenediyl group, and a butenediyl group.
Examples of the C2 to C20 alkynediyl group include ethynediyl and propynediyl groups.

  Moreover, as a substituent of C1-C5 alkylene group, C3-C6 cycloalkylene group, arylene group, C2-C20 alkene diyl group, C2-C20 alkyne diyl group, for example, methyl group, ethyl group, n-propyl group, isopropyl group C1-C20 alkyl group such as n-butyl group; C2-C20 alkenyl group such as vinyl group, propenyl group, butenyl; C1-C20 such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, butoxy group An alkoxy group; and the like.

  Specific examples of the bidentate phosphine ligand represented by the formula (4) include bisdiphenylphosphinomethane, bisdiphenylphosphinoethane, bisdiphenylphosphinopropane, bisdiphenylphosphinobutane, and bisdimethylphosphinoethane. And bisdimethylphosphinopropane.

  Furthermore, in the present invention, 2,2′-bis- (diphenylphosphino) -1,1′-binaphthyl (hereinafter referred to as BINAP) and a naphthyl ring of BINAP have a substituent such as an alkyl group or an aryl group. Also suitable are asymmetric ligands such as BINAP derivatives, BINAP derivatives having a fluorine substituent, and BINAP derivatives each having 1 to 5 substituents such as alkyl groups and alkoxy groups on two benzene rings on the phosphorus atom. It can be illustrated as a bidentate phosphine ligand.

  Specific examples thereof include 2,2′-bis- (di-p-tolylphosphino) -1,1′-binaphthyl (Tol-BINAP), 2,2′-bis [bis (3,5-dimethylphenyl) Phosphino] -1,1′-binaphthyl (Xylyl-BINAP), 1- [1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethyldiamine, 2,2′-bis- (dicyclohexylphosphino) -6,6 '-Dimethyl-1,1'-biphenyl, 2,3-bis- (diphenylphosphino) butane, 1-cyclohexyl-1,2-bis- (diphenylphosphino) ethane, 1-substituted-3,4-bis -(Diphenylphosphino) pyrrolidine, 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis- (diphenylphosphino) butane, 1,2-bis [ O-methoxyphenyl) phenylphosphino] ethane, substituted-1,2-bis (phosphorano) benzene, 5,6-bis- (diphenylphosphino) -2-norbornene, N, N′-bis- (diphenylphosphino) ) -N, N′-bis (1-phenylethyl) ethylenediamine, 1,2-bis- (diphenylphosphino) propane, 2,4-bis- (diphenylphosphino) pentane, [(5,6), ( 5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl] bis (diphenylphosphine), 1,2-bis (t-butylmethylphosphino) ethane, 2,4-bis- ( And diphenylphosphino) pentane.

  Many of the phosphine ligands (Px) are known substances and can be produced and obtained by known methods. Moreover, what is marketed can be used as it is or after purification if desired.

(2) Diamine ligand (A)
A represents a diamine ligand represented by the following formula (1) or (2).

In the formulas (1) and (2), R ¹ may have a C1-C20 alkyl group which may have a substituent, a C2-C20 alkenyl group which may have a substituent, or C3 which may have a substituent. -C8 cycloalkyl group, the C7-C20 aralkyl group which may have a substituent, the aryl group which may have a substituent, or the heterocyclic group which may have a substituent is represented.

Examples of the C1-C20 alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group, and a hexyl group. Preferably, it is a C1-C6 alkyl group.
Examples of the C2-C20 alkenyl group include ethenyl group, n-propenyl group, isopropenyl group, n-butenyl group, sec-butenyl group, t-butenyl group, pentenyl group, hexenyl group, and preferably C2. A C6 alkenyl group.
Examples of the C3 to C8 cycloalkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.
Examples of the C7 to C20 aralkyl group include benzyl group, α-methylbenzyl group, α, α-dimethylbenzyl group, α-ethylbenzyl group, phenethyl group and the like.
Examples of the aryl group include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

  As the heterocyclic group, tetrahydrofuran-2-yl group, tetrahydrofuran-3-yl group, 2-furanyl group, 3-furanyl group, 1,3-oxazolin-2-yl group, 1,3-oxazolin-4-yl Group, 1,3-oxazolin-5-yl group, tetrahydrothiophen-2-yl group, tetrahydrothiophen-3-yl group, 2-thienyl group, 3-thienyl group, 1,3-thiazolin-2-yl group, 1,3-thiazoline-4-yl group, 1,3-thiazoline-5-yl group, imidazol-2-yl group, imidazol-4-yl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group , Indol-1-yl group, indol-2-yl group, indol-3-yl group, indol-4-yl group, indol-5-yl group and the like.

  Examples of the substituent for the C1-C20 alkyl group, C2-C20 alkenyl group, C3-C8 cycloalkyl group, C7-C20 aralkyl group, aryl group and heterocyclic group include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A halogen atom of: methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, t-butyl group, n-pentyl group, isopentyl group, neopentyl group, t-pentyl group, n -C1-C20 alkyl group such as hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-dodecyl group; vinyl group, n-propenyl group, isopropenyl group, n- Butenyl group, sec-butenyl group, t-butenyl group, 1,3-butadienyl group, n-pentenyl group, 2-pentenyl group, 3-pentenyl group, C2-C20 alkenyl group such as xenyl group; C3-C8 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; benzyl group, α-methylbenzyl group, α, α-dimethylbenzyl group, α- C7-C20 aralkyl groups such as ethylbenzyl group; aryl groups such as phenyl group, 1-naphthyl group, 2-naphthyl group; methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec- C1-C20 alkoxy groups such as butoxy group and t-butoxy group; acyl group; acyloxy group; heterocyclic group;

Examples of the acyl group include an acetyl group, a propionyl group, an isopropylcarbonyl group, a benzoyl group, and a phenylmethylcarbonyl group.
Examples of the acyloxy group include C1-C12 alkylcarbonyloxy groups such as an acetoxy group, a propionyloxy group, and an isopropylcarbonyloxy group;
Arylcarbonyloxy groups such as benzoyloxy group; aralkylcarbonyloxy groups such as phenylmethylcarbonyloxy group; and the like.
Heterocyclic groups include oxygen-containing heterocyclic groups such as furanyl group, pyranyl group, dioxolanyl group; sulfur-containing heterocyclic groups such as thienyl group; pyrrolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, thiazolyl group Group, isothiazolyl group, pyridyl group, pyradadyl group, pyrazinyl group, benzoimidazolyl group, benzopyrazolyl group, benzozothiazolyl group, quinolyl group, anthranyl group, indolyl group, phenantronylyl group, etc. And the like.
These substituents are not particularly limited in the position of substitution, the type of substituent, the number of substituents, and the like.

R ² and R ³ each independently represent a hydrogen atom, an optionally substituted C1-C20 alkyl group, a C2-C20 alkenyl group, a C3-C8 cycloalkyl group, or a C7-C20 aralkyl group. However, the case where R ² and R ³ are hydrogen atoms at the same time is excluded.
As C1-C20 alkyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, t-butyl group, pentyl group or its isomer, hexyl group or its isomer Etc., preferably a C1-C6 alkyl group.
Examples of the C2-C20 alkenyl group include ethenyl group, n-propenyl group, isopropenyl group, n-butenyl group, sec-butenyl group, t-butenyl group, pentenyl group, hexenyl group, and preferably C2. A C6 alkenyl group.
Examples of the C3 to C8 cycloalkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.
Examples of the C7 to C20 aralkyl group include benzyl group, α-methylbenzyl group, α, α-dimethylbenzyl group, α-ethylbenzyl group and the like.

  Examples of the substituent for the C1-C20 alkyl group, C2-C20 alkenyl group, C3-C8 cycloalkyl group, C7-C20 aralkyl group include halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom; Ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, t-butyl group, n-pentyl group, isopentyl group, neopentyl group, t-pentyl group, hexyl group, heptyl group, octyl group C1-C20 alkyl groups such as nonyl group, decyl group, dodecyl group; vinyl group, n-propenyl group, isopropenyl group, n-butenyl group, sec-butenyl group, t-butenyl group, 1,3-butadienyl group A C2-C20 alkenyl group such as n-pentenyl group, 2-pentenyl group, 3-pentenyl group, hexenyl group; A C3-C8 cycloalkyl group such as a pill group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group; a C7-C20 aralkyl group such as a benzyl group, an α-methylbenzyl group, an α, α-dimethylbenzyl group, an α-ethylbenzyl group; Aryl groups such as phenyl group, 1-naphthyl group, 2-naphthyl group; C1-C1 such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, t-butoxy group, etc. C20 alkoxy group; acyloxy group; or heterocyclic group; and the like.

Examples of the acyloxy group include C1-C12 alkylcarbonyloxy groups such as acetoxy group, ethylcarbonyloxy group, isopropylcarbonyloxy group; arylcarbonyloxy groups such as benzoyloxy group; aralkylcarbonyloxy groups such as phenylmethylcarbonyloxy group; Etc.
Heterocyclic groups include oxygen-containing heterocyclic groups such as furanyl group, pyranyl group, dioxolanyl group; sulfur-containing heterocyclic groups such as thienyl group; pyrrolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, thiazolyl group Group, isothiazolyl group, pyridyl group, pyradadyl group, pyrazinyl group, benzoimidazolyl group, benzopyrazolyl group, benzozothiazolyl group, quinolyl group, anthranyl group, indolyl group, phenantronylyl group, etc. And the like.
These substituents are not particularly limited in the position of substitution, the type of substituent, the number of substituents, and the like.
R ² and R ³ may be bonded together to form a ring.

Although the specific example of the diamine ligand A represented by the said Formula (1) and Formula (2) is shown to a 1st table | surface and a 2nd table | surface, it is not limited to these.
In Tables 1 and 2, the abbreviations have the following meanings.
n-: normal, i-: iso, t-: tertiary, c-Pr: cyclopropyl, c-Pen: cyclopentyl, c-Hex: cyclohexyl, Ph: phenyl, Fu: furyl, Py: pyridyl,

  The diamine ligand (A) used in the present invention is not particularly limited as long as it can stably form a ruthenium compound, but a ruthenium compound having excellent asymmetric hydrogenation catalytic activity is used. From the viewpoint of obtaining, it is preferably an optically active diamine ligand. Since the diamine ligand (A) used in the present invention has only one asymmetric carbon atom in the molecule in principle, it is relatively easy to synthesize an optically active diamine ligand.

Many of the diamine ligands (A) represented by the formula (1) or (2) are known substances, and can be produced and obtained by known methods. An example of the manufacturing method is shown below. According to (Production route 1), in formula (1), diamine ligands (1-1) having various substituents R ¹ can be obtained. According to (Production route 2), in formula (2), a diamine ligand (2-1) having various substituents R ¹ can be obtained. Moreover, according to (Production route 3), the diamine ligand (1-2) having various substituents R ² and R ³ in the formula (1) can be obtained.
In the following (Production Route 1), the amino alcohol (a) as a starting material can be derived from a readily available α-amino acid by a known method.

(Wherein R ¹ and R ² represent the same meaning as described above, Boc represents a t-butoxycarbonyl group, Ms represents a trifluoromethanesulfonyl group, Me represents a methyl group, and * represents an optically active carbon. Represents an atom.)

  In the ruthenium compound of the present invention, a phosphine ligand (Px) and a diamine ligand (A) are reacted with zero-valent, monovalent, divalent, trivalent, and higher-valent ruthenium simple substance or ruthenium compound. Can be manufactured. Among them, Angew. Chem. Int. Ed. 37, 1703 (1998), a method using a divalent ruthenium complex is simple. That is, it can be manufactured by adding a diamine compound after heating a solvent solution of a divalent ruthenium-halide complex and a bidentate phosphine ligand.

Hereinafter, a method for producing a ruthenium compound when a divalent ruthenium-halide complex is used as a starting material will be described in more detail.
First, a divalent ruthenium-halide complex as a starting material and a phosphine ligand (Px) are reacted by heating in a solvent to obtain a corresponding phosphine-ruthenium-halide complex.

  The divalent ruthenium-halide complex of the starting material is not particularly limited as long as it is a ruthenium complex having a ligand that can be substituted with the phosphine ligand (Px) and the diamine ligand (A). .

  Specific examples include [ruthenium dichloride (norbornadiene)] polynuclear, [ruthenium dichloride (cyclooctadiene)] polynuclear, halogens coordinated with dienes such as [bis (methylallyl) ruthenium (cyclooctadiene)]. Ruthenium fluoride compounds; [ruthenium dichloride (benzene)] dinuclear, [ruthenium dichloride (p-cymene)] dinuclear, [ruthenium dichloride (trimethylbenzene)] dinuclear, [ruthenium dichloride (hexamethyl) Benzene)] ruthenium halides coordinated with an aromatic compound such as a dinuclear compound.

  The amount of the phosphine ligand (Px) used is usually 2 to 3 moles, preferably 2 moles when Px is a monodentate ligand with respect to 1 mole of ruthenium-halide complex. In the case of a ligand, it is usually 1 to 2 moles, preferably equimolar.

  Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; dichloromethane, chloroform, trichloromethane, carbon tetrachloride, and 1,2-dichloroethane. Halogen ethers such as diethyl ether, tetrahydrofuran (THF), ethers such as 1,2-dimethoxyethane and 1,4-dioxane; alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol and benzyl alcohol N, N-dimethylformamide (DMF), N, N-dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, hexamethylphosphoric triamide Amides such as (HMPT); Acetonitrile, nitriles such as benzonitrile; dimethyl sulfoxide (DMSO) and the like. These solvents can be used alone or in admixture of two or more.

  The amount of the solvent used is usually in the range of 1 ml to 100 ml, preferably 1 ml to 10 ml, with respect to 1 g of the substrate. The reaction temperature is usually in the range of 0 to 200 ° C, preferably room temperature to 100 ° C.

Next, the obtained phosphine-ruthenium-halide complex is reacted with the diamine compound (A) to obtain a corresponding amine-phosphine-ruthenium-halide complex.
The usage-amount of the diamine compound (A) used for this reaction is 1-2 times mole normally with respect to a phosphine-ruthenium-halide complex, Preferably it is equimolar.
The reaction temperature is usually in the range of −100 to + 200 ° C., preferably −10 to + 50 ° C.

  An amine-phosphine-ruthenium-halide complex can also be obtained by allowing a diamine compound (A) to act on a phosphine-ruthenium-halide complex isolated in advance under the same conditions as described above.

  Next, by reacting the obtained amine-phosphine-ruthenium-halide complex with a base in a solvent, among the compounds represented by the formula (I), X = Y = H 2 amine-phosphine-ruthenium hydride A complex can be obtained.

  Examples of the base used include triethylamine, diisopropylethylamine, pyridine, 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,4-diazabicyclo [5,4,0] unde-7-ene (DBU). Organic bases such as sodium methoxide, sodium ethoxide, potassium t-butoxide, magnesium ethoxide; organolithium compounds such as n-butyllithium and lithium diisopropylamide (LDA); sodium hydroxide, water Alkali metal hydroxides such as potassium oxide; carbonates such as potassium carbonate and sodium carbonate; metal hydrides such as sodium hydride;

The amount of the base used is usually in the range of 2 to 10,000 times mol, preferably 2 to 40 times mol, of the amine-phosphine-ruthenium-halide complex.
Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; dichloromethane, chloroform, trichloromethane, carbon tetrachloride, and 1,2-dichloroethane. Halogen ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, etc .; alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol, benzyl alcohol; acetonitrile, Nitriles such as benzonitrile; Amides such as DMF, N, N-dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone; Can be mentioned. These solvents can be used alone or in admixture of two or more.

  The usage-amount of a solvent is 1 ml-10L with respect to 1g of amine-phosphine-ruthenium-halide complexes, Preferably it is the range of 1 ml-1L. The reaction temperature is usually in the range of −100 to + 200 ° C., preferably −10 to + 50 ° C.

  In the formula (I), a ruthenium compound in which X and / or Y is a carboxyl group, a hydroxyl group, or an alkoxy group is an amine-phosphine-ruthenium-halide complex obtained by the above method or the like, and RCOONa or RONa (R is an alkyl group). It can be obtained by reacting.

  As described below, the ruthenium compound of the present invention obtained as described above can be obtained with high selectivity and high yield of the corresponding optically active alcohol compound from the carbonyl compound using an inexpensive hydrogen source such as hydrogen gas. It is useful as an asymmetric hydrogenation catalyst that can be produced.

2) Method for Producing Optically Active Alcohol Compound The method for producing an optically active alcohol compound of the present invention is characterized by hydrogenating a carbonyl compound in the presence of the ruthenium compound of the present invention.
In the method for producing an optically active alcohol compound of the present invention, a base is optionally added to a carbonyl compound serving as a substrate in the presence of the ruthenium compound represented by the formula (I), and hydrogen gas or hydrogen at a predetermined pressure is added. It is carried out by asymmetric hydrogenation in the presence of a donor.

  In the present invention, (i) a ruthenium complex (or ruthenium salt), a phosphorus compound and a diamine compound are separately added to the reaction system, or (ii) a ruthenium complex (or ruthenium salt) having a phosphine ligand and a diamine compound Are separately added to the reaction system, a base is added as necessary to form a ruthenium compound, and then the substrate is added in situ without removing the ruthenium compound from the reaction system. An asymmetric hydrogenation reaction can also be performed.

  When an optically active phosphine ligand (Px) and an optically active diamine ligand (A) are used as the ruthenium ligand, the phosphine ligand (Px) having any absolute configuration and the diamine configuration Depending on whether the ligand (A) is used in combination, the asymmetric hydrogenation catalytic activity of the obtained ruthenium compound (stereoselectivity of the resulting optically active alcohol, reaction yield, etc.) may differ. In addition, the asymmetric hydrogenation catalytic activity of the obtained ruthenium compound may differ depending on the type of substituent of the nitrogen atom of the diamine ligand (A). Therefore, when preparing the ruthenium compound of the present invention, the phosphine ligand (Px) and the diamine ligand (A) are appropriately selected and used in combination according to the type of the target optically active alcohol. There is a need.

  The amount of the ruthenium compound represented by the formula (I) used as the catalyst varies depending on the size of the reaction vessel and the catalytic activity, but is usually 1 with respect to the condensed carbonyl compound or α-diaminocarbonyl compound as the reaction substrate. / 50 to 1 / 2,000,000 times mole, preferably 1/500 to 1 / 500,000 times mole.

  Examples of the base used include organic bases such as triethylamine, diisopropylethylamine, pyridine, DABCO and DBU; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, magnesium methoxide and magnesium ethoxide; n- Organic lithium compounds such as butyl lithium; lithium amides such as LDA and lithium bistrimethylsilylamide; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth such as magnesium hydroxide and calcium hydroxide Alkali metal carbonates such as sodium carbonate and potassium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; Alkaline earth metals such as magnesium carbonate and calcium carbonate Genus carbonate; sodium hydride, metal hydrides such as calcium hydride; and the like.

  The addition amount of the base is usually in the range of 2 to 500,000 times mol, preferably 2 to 5,000 times mol of the ruthenium compound.

  The present invention can be carried out in a suitable solvent. The solvent to be used is not particularly limited as long as it can solubilize the substrate and the catalyst. Specific examples thereof include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol and benzyl alcohol; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane and hexane; dichloromethane Halogen ethers such as chloroform, trichloromethane, carbon tetrachloride, 1,2-dichloroethane; ethers such as diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane; DMF, N, N— Use amides such as dimethylacetamide, 1,3-dimethylimidazolidine, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone and HMPT; nitriles such as acetonitrile and benzonitrile; use DMSO and the like Can do. These solvents can be used alone or in admixture of two or more. Among these solvents, the use of alcohols is preferred because the reaction product is an alcohol compound.

  The amount of solvent used depends on the solubility and economics of the carbonyl compound, and in some cases, the reaction proceeds even without solvent or close to high dilution conditions. The range is from 10,000 to 10,000 parts by weight, preferably from 20 to 1,000 parts by weight.

  The hydrogen pressure is usually in the range of 1 to 200 atm, preferably 3 to 50 atm. As the hydrogen donor, for example, a hydrogen storage alloy or diimide can be used. On the other hand, it is usually in the range of 1 to 100 times equivalent.

  The reaction temperature is usually in the temperature range of −50 to + 100 ° C., preferably 25 to 40 ° C. Moreover, although reaction time is dependent on reaction conditions, such as a reaction substrate density | concentration, temperature, and pressure, it is normally several minutes-several days. Although there is no restriction | limiting in particular as a reaction format, For example, it can implement also in a batch type and a continuous type.

After completion of the reaction, the desired product can be obtained by isolation and purification by ordinary organic synthetic chemical techniques.
The structure of the target product can be determined by known analytical means such as ¹ H-NMR, optical rotation measurement, liquid chromatography, gas chromatography and the like.

EXAMPLES Next, although an Example demonstrates this invention in detail, this invention is not limited to these.
In addition, the apparatus used for the measurement of the physical property in each Example is as follows.
¹ H-NMR spectrum: GEMINI-300 (300 MHz), manufactured by Varian, and JNM-GSX-400 (400 MHz), JEOL Ltd. high performance liquid chromatography: LC-10Advp, SPD-10Avp, manufactured by Shimadzu Corporation Gas chromatography: GC-17A, C-R7A Plus, manufactured by Shimadzu Corporation

Example 1 Synthesis of RuCl ₂ [(S) -binap] [(R) -2-dimethylamino-1-phenylethylamine] Org. Synth. , According to the method of 71, 1 (1993), [RuCl ₂ (S) -binap] (dmf) n (binap is 2,2'-bis - a (diphenylphosphino) -1,1'-binaphthyl, dmf is Dimethylformamide is represented respectively, and the same applies hereinafter).
Next, argon-substituted 100 ml Schlenk was added to [RuCl ₂ (S) -binap] (dmf) n (0.47 g, 0.5 mmol), (R) -2-dimethylamino-1-phenylethylamine (0.1 g, 0.6 mmol) and 3 ml of degassed dimethylformamide were added and stirred at room temperature for 1 hour. Dimethylformamide was distilled off, and the precipitated solid was washed with diethyl ether to quantitatively obtain the desired product.
³¹ P-NMR (CDCl ₃ , δ ppm) 51.0, 36.6 (d, J = 31 Hz)

Example 2 Synthesis of 1- (S) -phenylethanol 0.1 ml of 1M potassium hydroxide isopropanol solution, 3.5 μl of (R) -2-dimethylamino-1-phenylethylamine and 0.60 g (5 mmol) of acetophenone in 3 ml of isopropanol And degassed. RuCl ₂ [(S) -tolbinap] (dmf) n (tolbinap represents 2,2′-bis- (di-p-tolylphosphino) -1,1′-binaphthyl, also abbreviated as Tolbinap. The same applies hereinafter. ) 10 mg (0.01 ml) was added and dissolved. Next, the whole volume was transferred to an autoclave, and stirred at room temperature for 1 hour under a hydrogen atmosphere of 8 atm. The reaction liquid was measured by gas chromatography (mobile phase: helium, column: CP-Chiralcel-Dex CB, manufactured by Chrome Pack Co., Ltd.), and the conversion was 99% or more and the optical purity was 91% ee.

  In Example 2, the diamine was replaced with (R) -2-dimethylamino-1-phenylethylamine, and those shown in Tables 3 to 5 were used, except that Tolbinap shown in Tables 3 to 5 was used. Were operated in the same manner as in Example 2. Tables 3 to 5 show the absolute configuration (config.) And optical purity (% ee) of the reaction product. The conversion rate (% conv.) Was 99% unless otherwise indicated.

Example 3 Synthesis of 1- (S) -phenylbutanol 0.1 ml of 1M potassium hydroxide isopropanol solution and 0.74 g (5 mmol) of butyrophenone were added to 3 ml of isopropanol and deaerated. RuCl ₂ [(S) -binap] [(R) -2-dimethylamino-1-phenylethylamine] 9.6 mg (0.01 ml) was added and dissolved, then transferred to an autoclave, and at room temperature under a hydrogen atmosphere of 8 atm. Stir for 1 hour. The reaction solution was concentrated and subjected to silica gel column chromatography to obtain 0.68 g (yield 91%) of the desired product. The optical purity of this product was 90% ee as measured by high performance liquid chromatography (mobile phase: n-hexane / isopropanol = 9/1, column: Chiralcel OD-H, manufactured by Daicel Chemical Industries, Ltd.).

  In Example 3, operation was performed in the same manner as in Example 3 except that the carbonyl compound shown in Table 6 was used instead of butyrophenone. Table 6 shows the optical purity (% ee) and yield (% conv.) Of the reaction product.

Example 4 Production of optically active-1-phenyl-2- (N-methyl-N-benzoylamino) -1-propanol

Under an argon atmosphere, 0.27 g (1 mmol) of 1-phenyl-2- (N-methyl-N-benzoyl) aminopropan-1-one was added to a simple autoclave (capacity 100 ml). A 0.1 ml solution of 0.1 M potassium hydroxide isopropanol was dissolved in 3 ml of isopropanol, degassed, and then RuCl ₂ [(S) -binap] [(R) -2-dimethylamino-1-phenylethylamine] 5 mg (0 0.005 mmol) was added, dissolved and transferred to an autoclave. Hydrogen was injected into the reaction system to 12 atm and stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give (1R, 2R) -1-phenyl-2- (N-methyl-N-benzoylamino) -1 -Propanol was obtained quantitatively.
The optical purity and diastereomeric purity of this product were measured by high performance liquid chromatography (mobile phase: n-hexane / ethanol = 15/1, column: Chiralcel OJ, manufactured by Daicel Chemical Industries, Ltd.). % Ee and the diastereomeric purity was 99% de or higher.

Claims (6)

Formula (I)

[Wherein, X and Y each independently represent a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group or a C1-C20 alkoxy group.
Px represents a phosphine ligand, and n represents 1 or 2.
A represents a diamine ligand represented by the following formula (1) .

[In the formula, R ¹ is (halogen atom, C3-C8 cycloalkyl group, C1-C20 alkoxy group, phenyl group, 1-naphthyl group, 2-naphthyl group, acetyl group, propionyl group, isopropionylcarbonyl group, benzoyl Group, a phenylmethylcarbonyl group, a C1-C12 alkylcarbonyloxy group, an oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, or a nitrogen-containing heterocyclic group),
(Halogen atom, C1-C20 alkyl group, C2-C20 alkenyl group, C3-C8 cycloalkyl group, C1-C20 alkoxy group, acetyl group, propionyl group, isopropionylcarbonyl group, benzoyl group, phenylmethylcarbonyl group, C1- A C7-C20 aralkyl group optionally substituted with a C12 alkylcarbonyloxy group, an oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, or a nitrogen-containing heterocyclic group, or
(Halogen atom, C1-C20 alkyl group, C2-C20 alkenyl group, C3-C8 cycloalkyl group, C7-C20 aralkyl group, C1-C20 alkoxy group, C7-C20 aralkyl group, phenyl group, 1-naphthyl group, 2 -Naphtyl group, acetyl group, propionyl group, isopropionylcarbonyl group, benzoyl group, phenylmethylcarbonyl group, C1-C12 alkylcarbonyloxy group, oxygen-containing heterocyclic group, sulfur-containing heterocyclic group, or nitrogen-containing heterocyclic group) Represents an optionally substituted phenyl group,
R ^{2, R 3} represents a methyl group. R ² and R ³ may be bonded together to form a ring. ]
Ruthenium compounds represented by The ruthenium compound according to claim 1, wherein Px is an optically active phosphine ligand.   The ruthenium compound according to claim 1, wherein A is an optically active diamine ligand. Wherein A is the formula (1), a ruthenium compound according to any one of claims 1 to 3 R ¹ is a diamine ligand phenyl group which may have a substituent.   An asymmetric hydrogenation catalyst comprising the ruthenium compound according to any one of claims 1 to 4.   A method for producing an optically active alcohol compound, comprising hydrogenating a carbonyl compound in the presence of the ruthenium compound according to claim 1.