WO2006137165A1

WO2006137165A1 - Hydrogenation catalyst and process for producing alcohol compound therewith

Info

Publication number: WO2006137165A1
Application number: PCT/JP2005/011674
Authority: WO
Inventors: Noriyuki Utsumi; Kunihiko Murata; Kunihiko Tsutsumi; Takeaki Katayama; Takeshi Ohkuma; Ryoji Noyori
Original assignee: Kanto Kagaku Kabushiki Kaisha; Nagoya Industrial Science Research Institute
Priority date: 2005-06-20
Filing date: 2005-06-20
Publication date: 2006-12-28

Abstract

An optically active alcohol is produced by incorporating in a solvent a ketone compound together with a Lewis acid and a ruthenium complex of the formula: and mixing them together in the presence of hydrogen to thereby hydrogenate the ketone compound.

Description

Specification

Hydrogenation catalyst and process for producing alcohol compound using the same

The present invention relates to a novel hydrogenation catalyst and a method for producing an alcohol compound using the same. Background art

So far, various methods for producing optically active alcohols using metal complexes as catalysts have been reported. In particular, a method for synthesizing optically active alcohols from ketone compounds by a reductive method using a ruthenium complex as a catalyst in the presence of a base has been studied very vigorously.

As for asymmetric hydrogenation using hydrogen as a reducing agent and asymmetric hydrogenation of canes to obtain optically active alcohols, and catalysts, see, for example, JP-A-8-2 2 5 4 6 6 In the presence of a base, using BINAP (2,2, -bis (diphenylphosphino) -1,1,1'-binaphthyl) and DMF coordinated to ruthenium and diphenylethylenediamine as catalyst Examples of producing optically active alcohols by hydrogenating ketone compounds have been reported. However, depending on the structure of the cane compound, the hydrogenation reaction may not proceed efficiently or the enantiomeric excess may be insufficient. In addition, in the above catalyst system, since the reaction was carried out under basic conditions, it was not possible to hydrogenate ketone compounds that are unstable to bases or that have acidic hydrogen. Several attempts have been made to solve these problems.

For example, in Japanese Patent Application Laid-Open No. 2 093-1 0 4 993, tetrahydroporate of an asymmetric ruthenium metal complex in which a diphosphine compound such as BINAP and a diamine compound are coordinated to ruthenium is used as a catalyst. , Pressurized water Several examples have been reported in which an optically active alcohol was produced by hydrogenating a base-labile cane compound in 2-propanol without adding a base. Specifically, the corresponding optically active alcohols are produced from 4-acetyl benzoyl benzoate, 3-nonen-2-one and the like.

However, in the catalyst described in Japanese Patent Application Laid-Open No. 2000-103-93, the yield and enantiomeric excess may be low depending on the reaction substrate, and the structure of the applicable cane compound Was limited.

For catalytic asymmetric hydrogenation, a method using alcohol or formic acid as a reducing agent, that is, catalytic asymmetric reduction reaction, has been reported. In particular, the performance of an asymmetric ruthenium catalyst having an amine ligand having a sulfonamido group as an anchor (Japanese Patent Laid-Open Publication No. H11-32 26489) is notable. In addition to this, a similar catalytic system (Cliem. Commun. 1996, 223. Organome tal 1 ics 1996, 15, 1087.) having a ruthenium monoamine complex as a basic skeleton has been reported. Similarly, rhodium and iridium catalysts having metal-amine bonds (J. Org. Chem. 1999, 64, 2186.) have also been reported. These asymmetric metal catalysts can asymmetrically reduce more types of ketone substrates than the above hydrogenation catalysts, but have a low hydrogen activation ability, and 2-propanoyl as a hydrogen source. Only organic compounds such as formic acid can be used. In addition, more catalysts are required than asymmetric hydrogenation using hydrogen. In addition, when formic acid is used, there are problems such as the problem of corrosion of the reaction kettle. Asymmetric reduction of phenasyl chloride using formic acid as a reducing agent in the presence of a catalyst with rhodium as the central metal has been reported (W 0 0 2 0 0 2 no 0 5 1 7 8 1). Problems include activity and the use of corrosive formic acid.

Therefore, asymmetric hydrogenation of various ketone substrates using hydrogen as a reducing agent has been required to be carried out with high selectivity and high efficiency. Disclosure of the invention

As described above, in the conventional hydrogenation catalyst method, although the structure of the applicable cane compound is limited and it is industrially useful, 2-chloro- 1-phenylethanol is used. Alcohols with structures such as 4- and chromanol have not been able to efficiently produce these optically active alcohols, which has been a major issue. On the other hand, although a method for asymmetric reduction of these canes using formic acid or the like as a reducing agent is known, the amount of catalyst used is large, so that it is efficient and corrosive formic acid. There was a problem such as using.

The present invention has been made to solve such problems, and provides a hydrogenation catalyst useful in producing an alcohol compound that has been difficult to obtain so far, and an alcohol using the hydrogenation catalyst. It aims at providing the manufacturing method of a compound.

In order to achieve such an object, as a result of intensive research, the present inventors have made a Lewis acid act on a Group 8 or Group 9 transition metal complex having a metal amide bond, thereby producing hydrogen. We found that a new catalyst with activation ability could be obtained. We also found that a new catalyst capable of activating hydrogen can be obtained by reacting Lewis acid with a Group 8 or Group 9 transition metal complex having an amine ligand. Here, Lewis acid is used in the sense of a compound that accepts electrons, and does not include a prested acid that releases protons. Although the mechanism of catalyst formation is being elucidated, the use of such a hydrogenation catalyst enables efficient hydrogenation of ketone substrates, especially high-tech Nancho selective hydrogenation, which is difficult with conventional hydrogenation catalysts. It has been found that it has progressed, and the present invention has been completed.

That is, the hydrogenation catalyst of the present invention has a group 8 or 9 having a metal amide bond. Group transition metal complexes and Lewis acids (excluding Brenstead acid that releases protons, the same shall apply hereinafter) or group 8 or group 9 transition metal complexes having metal amide bonds and Lewis acids. It was obtained by mixing. Alternatively, a group 8 or group 9 transition metal complex having an amine ligand and a Lewis acid are included, or a group 8 or group 9 transition metal complex having an amine ligand and a Lewis acid are mixed in advance. It was obtained by this. The method for producing an alcohol compound of the present invention is to obtain an alcohol compound by hydrogenating a ketone compound with such a hydrogenation catalyst. If the hydrogenation catalyst of the present invention is used, an alcohol compound that has been difficult to obtain can be produced.

Hereinafter, the present invention will be described in detail.

In the hydrogenation catalyst of the present invention, the group 8 or group 9 transition metal complex having a metal amide bond is preferably a compound represented by the following general formula (1). Here, the metal amide bond in the general formula (1) means a bond between M and NR ⁴ metal and nitrogen. In the hydrogenation catalyst of the present invention, the group 8 or group 9 transition metal complex having an amine ligand is preferably a compound represented by the following general formula (2). Here, the amine ligand of the general formula (2) means a coordinate bond between the metal of NHR ⁴ and nitrogen in X 丄.

Expression

Formula (2)

(In the general formula (1) or the general formula (2), R ¹ and R ² may be the same or different from each other, and may have a substituent, an alkyl group, a phenyl group, A group, a naphthyl group or a cycloalkyl group, or a part of the ring when bonded to each other to form an alicyclic ring,

R ³ is an alkyl group, a naphthyl group, a phenyl group, or camphor, which may have a substituent,

R ⁴ is a hydrogen atom or an alkyl group,

Ar is an optionally substituted benzene or an optionally substituted pentagen group bonded to M ¹ via a 兀 bond.

M ¹ is ruthenium, rhodium or iridium,

* Indicates an asymmetric carbon. ).

R ¹ and R ^{2 in the} general formula (1) and the general formula (2) are, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl And an alkyl group having 1 to 10 carbon atoms such as a group. In addition, phenyl groups having 1 to 5 carbon atoms such as phenyl groups, 4-methylphenyl groups, 3,5-dimethylphenyl groups, halogen substitutions such as 4-fluorophenyl groups and 4-chlorophenyl groups And a phenyl group having an alkoxy group such as a 4-methoxyphenyl group. In addition, naphthyl group, 5,6,7,8-tetrahydro-1-naphthyl group, 5,6,7,8-tetrahydro-2-na Examples include a butyl group. Moreover, a cyclopentyl group, a cyclohexyl group, etc. are mentioned. Also,; R ¹ and R ² are also mentioned alicyclic ring having an unsubstituted or substituted group to form a ring, cyclopentane ring, for example the R ¹ and R ² to form a ring Examples include N-cyclohexane ring. Among these, as R ¹ and R ^2, it is preferable that both are phenyl groups, or a cyclohexane ring in which R ¹ and R ² are combined to form a ring. General Formula (1) (2) The alkyl group at R ³ in (2) is, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, etc. Of the alkyl group. These alkyl groups may have a substituent, for example, may have one or more fluorine atoms as a substituent. Examples of the alkyl group containing one or more fluorine atoms include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a pentafluoroethyl group. Examples of the naphthyl group which may have a substituent include, for example, an unsubstituted naphthyl group, a 5,6,7,8-tetrahydrone-1-naphthyl group, and a 5,6,7,8-tetrahydro-2. -Naphthyl group and the like. Examples of the optionally substituted phenyl group include unsubstituted phenyl group, 4-methylphenyl group, 3,5-dimethylphenyl group, 2,4,6-trimethylphenyl group, 2,4 , 6- 卜 Phenyl group having an alkyl group such as triisopropylphenyl group, 4-fluorophenyl group, phenyl group having a halogen substituent such as 4-chlorophenyl group, alkoxy such as 4-methoxyphenyl group And a phenyl group having a group.

Specific examples of R ⁴ in general formula (1) and general formula (2) include alkyl groups having 1 to 5 carbon atoms such as a methyl group and an ethyl group, and a hydrogen atom. Preferred is hydrogen.

Ar in general formula (1) and general formula (2) includes, for example, unsubstituted benzene, toluene, o-, m-, and P-xylene, o-, m-, and P-cymene. 1, 2, 3-, 1, 2, 4-, and 1, 3, 5, 5-trimethylbenzene, 1, 2, 4, 5-tetramethylbenzene, 1, 2, 3, 4-tetramethylbenzene And benzene having an alkyl group, such as Penyu-Methylbenzene and Hexamethylbenzene. Further, the cyclopentenyl group which may have a substituent includes a cyclopentaenyl group, a methylcyclopentenyl group, a 1,2-dimethylcyclopentenyl group, a 1,3-dimethylcyclopentenyl group, 1,2,3-trimethylcyclopentenyl group, 1,2,4trimethylcyclopentenyl group, 1,2,3,4-tetramethylcyclopentenyl group, and 1,2,3, Examples include 4,5-pentamethylcyclopentagenyl group.

M ^{1 in} general formula (1) and general formula (2) is a transition element of group 8 or group 9, among which ruthenium, rhodium and iridium are preferred. X ¹ in general formula (2) is anionic. For example, hydride group, bridged oxo group, fluorine group, chlorine group, bromine group, iodine group, tetrafluoroporate group, tetrahydroborate group, tetrakis [3,5-bis (trifluoromethyl) phenyl ] Porate group, acetooxy group, benzoyloxy group, (2, 6-dihydroxybenzoyl) oxy group, (2, 5-dihydroxybenzoyl) oxy group, (3-aminobenzoyl) oxy group, (2, 6 -Methoxybenzoyl) oxy group, (2,4,6-triisopropylbenzoyl) oxy group, 1-naphthalenecarboxylic acid group, 2-naphthalenecarboxylic acid group, trif Fluoroacetoxy group, trifluoro Examples include a romethanesulfonimide group, a nitromethyl group, a nitroethyl group, and a hydroxyl group. Among these, preferred as X ¹ are a hydride group, a hydroxyl group, a crosslinked oxo group, a fluorine group, a chlorine group, a bromine group and an iodine group.

The compounds represented by the general formula (1) and the general formula (2) can be regarded as a structure in which a bidentate ethylenediamine compound (RSSO sNH CHR ^ CHR SN HR ⁴ ) is bonded to a metal. In order to disclose the compounds represented by the general formula (1) and the general formula (2) more specifically, specific examples of the ethylenediamine compound are listed as follows. N- (p-toluenesulfonyl) -1,2,2-diphenylethylenediamine (T s DP EN), N-methanesulfonyl-1,2,2-diphenylethylenediamine (Ms DP EN), N -Methyl-N '-(p-toluenesulfonyl) -1, 2-diphenylethylenediamine, N- (p-methoxyphenylsulfonyl) -1, 2-diphenylethylenediamine, N -(p-alkenyl phenylsulfonyl)-1, 2-diphenylethylenediamine, N-trifluoromethanesulfonyl-1, 2-diphenylethylenediamine, N-(2, 4, 6- Trimethylbenzenesulfonyl) -1, 2-diphenylethylenediamine, N- (2,4,6-triisopropylbenzenesulfonyl) -1, 2-diphenylethylenediamine, N- (4-te rt-butylbenzenesulfonyl)-1, 2-diphenylethylenediamine, N-(2 -Naphthylsulfonyl) -1,2,2-diphenylethylenediamine, N- (3,5-dimethylbenzenesulfonyl) -1,2,2-diphenylethylenediamine, N-pentamethylbenzenesulfonyl-1,2-diphenyl Examples include ethylenediamine, 1,2-N-tosylcyclohexanediamine (T s CYDN), and the like. Of these, T s DP EN and T s CYDN are preferable. In the hydrogenation catalyst of the present invention, the Lewis acid is preferably a compound represented by the following general formula (3).

General formula (3) '

M ² _m X ² _n

(In the general formula (3), M ² is boron, aluminum, Keimoto scandia Jiumu, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, gallium, germanium, said thorium, Jirukoniu arm , Niobium, molybdenum, technetium, ruthenium, rhodium, paradium, silver, cadmium, indium, tin, antimony, lanthanum, cerium, prasedium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, dysprosium Ytterbium, lutetium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, thallium, lead, bismuth or actinoide In and, m is an integer of 1 or 2,

X ² is an anionic group, an alkyl group, or an optionally substituted phenyl group, which may be the same or different from each other, and n represents an integer of 2 to 14. )

—M ² in general formula (3) includes aluminum, boron, silicon, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, gallium, germanium, yttrium, and zirconium. Um, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, indium, tin, antimony, lanthanum, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, thallium, Examples include lead, bismuth, and lactide. Preferably, boron, scandium, Rum, lanthanide, and actinoid.

X ² in the general formula (3) may be the same or different from each other, and may be an anionic group, an alkyl group, or a phenyl group which may have a substituent, and n is 2-1 Indicates an integer of 4. Specific examples of X ² include chlorine group, bromine group, iodine group, triflate group, hydroxyl group, nitro group and sulfate group. Preferred are a chlorine group, a bromine group, an iodine group, and a triflate group, and most preferred is a triflate group.

Specific examples of the compound represented by the general formula (3) include scandium chloride, yttrium chloride, lanthanum chloride, cerium chloride, praseodymium chloride, neodymium chloride, samarium chloride, plutonium chloride, gadolinium chloride, holmium chloride, Ytterbium chloride, aluminum chloride, scandium bromide, yttrium bromide, lanthanum bromide, cerium bromide, praseodymium bromide, neodymium bromide, samarium bromide, plutonium bromide, gadolinium bromide, holmium bromide Ytterbium bromide, aluminum bromide, scandium iodide, yttrium iodide, lanthanum iodide, cerium iodide, praseodymium iodide, neodymium iodide, samarium iodide, plutonium iodide, gadolinium iodide, iodine Holmium, Ytterbium iodide, aluminum iodide, scandium triflate, yttrium triflate, lanthanum triflate, cerium triflate, praseodymium triflate, neodymium triflate, samarium refrigerate, plutonium refrigerate, gadolinium Triflutter, holmium triflate, ytterbium triflate, aluminum triflate, boron trifluoride, boron trichloride, boron tribromide, boron tribromide, triisopropyl borate, triphenyl boron, tris Fluorophenyl) boron and the like. Of these, scandium refractory, yttrium triflate, lantern triflate , Praseodymium triflate, samarium triflate, gadolinium triflate, ytterbium triflate and boron trifluoride are preferred.

As the hydrogenation catalyst of the present invention, a catalyst containing a group 8 or group 9 transition metal complex having a metal amide bond and a Lewis acid, or a group 8 or group 9 transition metal complex having an amine ligand is used. It is presumed that the actual hydrogenation catalyst will be generated in the hydrogenation reaction system when using a catalyst containing Lewis acid. That is, before carrying out the hydrogenation reaction, a group 8 or group 9 transition metal complex having a metal amide bond or an amine ligand, a reaction substrate, a Lewis acid, and a hydrogenation reaction solvent are added to a pressure resistant reaction vessel. The hydrogenation reaction is then carried out by stirring in the presence of hydrogen or a compound that donates hydrogen.

As the hydrogenation catalyst of the present invention, a group 8 or group 9 transition metal complex having a metal amide bond and a Lewis acid mixed in advance, or a group 8 or group 9 transition having an amine ligand are used. When using a mixture of a metal complex and a Lewis acid in advance, first prepare a hydrogenation catalyst by adding the metal complex, Lewis acid and reaction solvent and stirring, and prepare the prepared hydrogenation catalyst and reaction. The hydrogenation reaction is performed by adding the substrate and the hydrogenation reaction solvent to the pressure-resistant reaction vessel, and then stirring in the presence of hydrogen or a compound that donates hydrogen. As a solvent used for preparing the catalyst, a protic solvent to an aprotic solvent can be used. Specifically, methanol, ethanol, 2-propanol, water, toluene, tetrahydrofuran, acetone, and N, N-dimethylformamide is used. Of these, the use of a protic solvent is preferable, and methanol and ethanol are more preferable. When a protic solvent is used, the reaction time is not particularly limited, and the reaction is often completed within a few minutes to an hour at room temperature. Group 8 or 9 transition metal complexes with metal amide bonds or amine coordination The amount of Lewis acid used for a group 8 or 9 transition metal complex with a ligand varies depending on the concentration of the hydrogenation reaction to be performed and the substrate-catalyst ratio, but is generally from 0.1 to 10 molar equivalents. It is.

A method for preparing a compound represented by the general formula (1), which is an example of a group 8 or group 9 transition metal complex having a metal amide bond, is described in Angew. Chem., Int. Ed. Engl. Vol. 36, p285 (1997) and J. Org. Chem. Vol. 64, _P 2 186 (1999). Specifically, a transition metal complex such as a ruthenium allene complex, a pentamethylcyclopentagenyl rhodium complex, or a pentamethylcyclopentadiene dilysium complex and a sulfonyldiamine ligand in the presence of an excessive strong base such as KOH. It can be synthesized by reacting.

It is also an example of a group 8 or group 9 transition metal complex having an amine ligand. The method for preparing the compound represented by the general formula (2) is described in Angew. Chem., Int. E d. Engl. Vol. 36, p285 (1997) and J. Org. Chem. Vol. 64, p2186 (199 9). Specifically, transition metal complexes such as ruthenium allene complex, pentamethylcyclopentanegenyl rhodium complex, pentamethylcyclopentanegenyl iridium complex, and sulfonyldiamine ligands, and weak bases such as triethylamine are present. It can be synthesized by reacting below. It can also be synthesized by the reaction of a metal amide complex having a sulfodilamine ligand and hydrogen chloride.

In the method for producing an alcohol compound of the present invention, an alcohol compound is obtained by hydrogenating a cane compound with the hydrogenation catalyst of the present invention described above in the presence of hydrogen or a compound that donates hydrogen. For example, a hydrogenation catalyst and a cane compound are placed in a solvent, mixed in the presence of hydrogen or a compound that donates hydrogen, and the cane compound is hydrogenated to obtain an alcohol compound.

The amount of catalyst used at this time is the amount of the ketone compound relative to the metal complex. If S / C is expressed as S / C (S is a substrate, C is a catalyst), SZC is not particularly limited, but considering practicality, it should be used in the range of 10 to 100, 0 0 0 It is preferable to use in the range of 5 0 to 1 0, 0 0 0. Examples of the hydrogenation reaction solvent include alcohol solvents such as methanol, ethanol, 2-propanol, 2-methyl-2-propanol, 2-methyl-2-butanol, tetrahydrofuran (THF), and jetyl ether. Ether solvents such as DMSO, DMF, and acetonitrile, aromatic hydrocarbon solvents such as toluene and xylene, aliphatic hydrocarbon solvents such as pentane and hexane, halogen-containing hydrocarbons such as methylene chloride A solvent, water or the like can be used alone or in combination. In addition, a mixed solvent of the solvent exemplified above and other solvents can also be used. Of these solvents, alcohol-based solvents are preferable, and methanol and ethanol are more preferable in order to proceed the reaction efficiently. The amount of the solvent is determined by the solubility and economics of the reaction substrate. For example, in the case of methanol, the concentration of the hydrogenation reaction is from a low concentration of 1% by weight or less to 99% by weight or more of almost no solvent. The reaction can be carried out in the state, and the reaction is preferably carried out at a concentration of 5 to 80% by weight. Under these high concentration conditions, few examples of hydrogenation reactions proceeding with high reactivity are known, and it is possible to increase the production amount per batch of the hydrogenation reaction. Very advantageous.

The hydrogen pressure is not particularly limited, but can be carried out in the range of 1 to 200 atm. In view of economy, the range of 5 to 150 atm is preferable. The reaction temperature is not particularly limited, but in consideration of economy, it can be carried out in the range of 150 to 100 ° C, preferably in the range of 30 to 60, More preferably, it is carried out in the range of 60 ° C. The reaction time depends on the reaction conditions such as the type of reaction substrate, concentration, szc, temperature, and pressure, and the type of catalyst. Therefore, various conditions may be set so that the reaction is completed within a few minutes to several days, and it is particularly preferable to set the conditions so that the reaction is completed within 5 to 24 hours. Further, the reaction product can be purified by a known method such as column chromatography, distillation, recrystallization and the like.

In addition, in the method for producing an optically active alcohol in the present invention, it is not essential to add a base to the reaction system, so that the hydrogenation reaction of the ketone compound proceeds rapidly without adding a base. However, the addition of a base is not excluded. For example, a small amount of a base may be optionally added depending on the structure of the reaction substrate and the purity of the reagent used.

In the hydrogenation catalyst of the present invention, the two asymmetric carbons in the compounds represented by the general formulas (1) and (2) are both in the (R) form in order to obtain an optically active alcohol compound. Or both must be in (S) form. By selecting either of these (R 1) or (S 2) isomers, an optically active alcohol having a desired absolute configuration can be obtained with high selectivity. In the case where it is desired to produce a racemic alcohol or an achiral alcohol, both of these chiral carbons do not need to be in the (R) form or (S) form, and may be either independently.

As described above, in the method for producing an alcohol compound of the present invention, when an optically active alcohol compound is obtained, the ketone compound is hydrogenated without adding a base. However, the corresponding optically active alcohol compound can be obtained by hydrogenation. Therefore, according to the method for producing an alcohol compound of the present invention, it can be applied to a ketone compound having a wider structure as compared with a conventionally known method using a hydrogenation catalyst not containing a base. The reaction is not affected by impurities and proceeds with good reproducibility, and the target substance can be obtained with high optical purity and high yield. Moreover, according to the hydrogenation catalyst of the present invention, for example, conventional hydrogen Hydrogenate cyclic ketones that could not be reduced efficiently with a fluorination catalyst to produce optically active cyclic alcohols, or ketones having an olefin moiety or an acetylene moiety (especially α, / 3-bonds are olefin moieties or Hydrogenation of an acetylene moiety (ketone) to produce an optically active alcohol having an olefin moiety or an acetylene moiety, a hydrogenated ketone having a hydroxyl group to produce an optically active alcohol having a hydroxyl group, or a halogen substituent. Hydrogenated ketones (especially ketones having an eight-rogen substituent at the α-position) to produce optically active alcohols having halogen substituents, hydrogenated chromanone derivatives to produce optically active chromanols, hydrogenated diketones To produce optically active diols or hydrogenate ketoesters to produce optically active diols. The optically active hydroxyamide can be produced by producing an active hydroxy ester or by hydrolyzing ketoamide, and the method described in the present invention is extremely useful. Typical examples of ketone compounds applicable to the process for producing the optically active alcohol of the present invention are listed below.

Example

Hereinafter, the present invention will be described in more detail with reference to examples. Of course, the present invention is not limited to the following examples. The hydrogenation reaction of a ketone compound in the present invention can be performed in a batch type. It can also be implemented in a continuous mode.

In the following examples, the solvent used for the reaction was dried and degassed. NMR was measured using JNM-LA400 (400 Mh ζ, manufactured by JEOL Ltd.) and JNM-LA500 (500 MHz, JEOL Ltd.). In iHNMR ¹³ C NMR, tetramethylsilane (TMS) was used as the internal standard substance, and the signal was δ = 0 (<5 is chemical shift). The optical purity was measured by gas chromatography (GC) or high performance liquid chromatography (HPLC). GC was measured using C hirasi 1-DEXCB (0.25 mm X 25 m, DF = 0.25 m) (CHR OM PACK), and HPLC was CHI RAL CEL OD (0.4 6 c mX 25 cm), CHI RAL CELOB (0.4 6 c mX 25 cm), CH I RAL CELOJ-H (0.4 6 cm X

25 cm) (manufactured by Daicel). Specific rotation was measured using DIP-3570 (manufactured by JASCO Corporation). In addition, the metal complexes represented by the above general formulas (1) and (2) are known from Angew. Chem., Int. Ed. Engl. Vol. 36, p285 (1997), and J. Org. Chem. Vol. , p2186 (1999).

[Example 1]

-Synthesis of (R) -2 -chloro-1-phenylethanol by hydrogenation of chloroacetophenone

In stainless steel clave, Ru [(S, S)-T sdpen] (p-c ym ene) (1.2 mg, 2 ^ mo 1), Y b (OT f) 3 (1.2 4 mg, 2 mo 1), a-chloroacetophenone (0.

3 g, 2 mm o 1) was charged, and the atmosphere was replaced with argon. Methanol 4 ml was added, pressurized with hydrogen, and then replaced 10 times. Hydrogen was charged to 20 atm to start the reaction. After stirring at 30 ° C. for 15 hours, the reaction pressure was returned to normal pressure. From ¹ H NMR and GC analysis of the product, 95% ee (R) -2-chloro-1_phenylethanol was produced in 61% yield. The analysis results are as follows. ¹ HNMR (4 00 MHz, CDC 1 ₃ ) <5 2. 6 1 (d, J = 3 H z, 1 H, CHOH), 3.6 5 (dd, J = 9 H z, 1 1 H z, 1 H, C HH CI), 3. 75 (dd, J = 3 H z, 1 1 H z, 1 H, C HilC 1), 4. 9 1 (ddd, J = 3 H z, 3 H z, 9 H z, 1 H, C HO H), 7. 2 7-7. 3 9 (m, 5 H, aromatic H); GC (C hirasi 1-D EX CB; column temperature, 1 3 0 ° C; Injection temperature, 25 0 ° C; Detection temperature, 2 m 5; Helium pressure, l OO k Pa; (R) '-2-Black mouth-1-phenyl ethanol t _R , 1 7.0 min; (S)-2-black mouth-1-phenylethanol t _R , 15.7 min); specific rotation [a] ^{2 Q} _D — 4 6 ° (c 2. 8, C ₆ H _{1 2} ); literature values, [a] ² . _D — 4 8 ° (c 2. 8, C ₆ H _{1 2} ), (R), A 1 drich 2 0 0 5— 2 0 0 6 year catalog. R u [(S, S) -T sdpen] (p-c ym ene) was synthesized according to the technique described in the above-mentioned publicly known literature, and the specific procedure is shown below. First, in a Schlenk-type reaction tube purged with argon, [Ru C 1 ₂ (p-c ym ene)] ₂ (3 10 mg, 0.5 mmol), S, S)-T s DP EN (3 70 mg, 1 mm o 1), KOH (400 mg, 7 mm o 1), and methylene chloride 7 m 1 were charged. Subsequently, the mixture was stirred at room temperature for 5 minutes. 7 ml of water was added and stirred at room temperature for 5 minutes. The layers were separated, and the methylene chloride layer was washed with 7 ml of water. After adding C a H ₂ and drying, C a H ₂ was removed by filtration. Methylene chloride was distilled off under reduced pressure (I mmH g) and dried to obtain Ru [(S, S) -T sdpen] (p-cymene) 5 20 mg.

[Example 2-4] The reaction was carried out under the same conditions as in Example 1 except that the amount of Y b (OT f) ₃ was changed to synthesize (R) -2-2-chloro-1-phenylethanol. The results are summarized in Table 1. Thus, a wide range of molar equivalents of Y b (OT f) ₃ can be used for ruthenium.

table 1

0 — Ru catalyst 9 ¹ " ¹

+ Methanol _ph .C.

Example Yb (OTf) ₃ / Ru yield (%) ee (%)

2 1.5 100 96

3 2 100 95

4 3 87 96

Conditions: Ru [(S, S) -Tsdpen] (p-cymene) 2 μηιοΙ, ketone / CH ₃ OH = 0.3 g / 4 ml, S / C = 1000, H ₂ 20 atm, temp 30 ° C, time 15 h.

[Examples 5 to 6]

The reaction was carried out under the same conditions as in Example 1 except that S c (OT f) ₃ or BF ₃ '0 (C ₂ H ₅ ) ₂ was used instead of Y b (OT f) ₃ , and (R )-2-Chromium-1-Phenylethanol was synthesized. The results are summarized in Table 2. As described above, various types of Lewis acid used in combination with the metal complex can be used.

Example Ru catalyst yield (%) ee (%)

5 Ru [(S, S) -Tsdpen] (p-cymene), Sc (OTf) ₃ 100 95

6 Ru [(S, S) -Tsdpen] (p-cymene), BF ₃ '0 (C ₂ H ₅ ) 2 88 94

Conditions: Ru cat 2 μηιοΙ, ketone / CH ₃ OH = 0.3 g / 4 ml, S / C

H ₂ 20 atm, temp 30 ° C, time 15 h.

[Example 7]

-Synthesis of (S)-2-chloro-1-phenyanol by hydrogenation reaction of chloroacete phenone

In stainless steel clave, Ru [(R, R)-T sdpen] (mesity 1 ene), 1.3 mg, 2 _im ol), Y b (〇 T f) 3 (1. 2 4 mg , 2 urn o 1), a-chloroacetophenone (0.9 g, 6 mm o 1), and substituted with argon. Methanol 5.9 m 1 was added, pressurized with hydrogen, and replaced 10 times. Hydrogen was charged to 100 atmospheres and the reaction was started. After stirring at 30 ° C for 15 hours, the reaction pressure was returned to normal pressure. From ¹ HNMR and GC analysis of the product, 95% ee (S) -2-cyclohex- ^1- phenylethanol was produced in 47% yield.

[Example 8]

a:-Synthesis of (R)-2 -chloro-1 -phenylethanol by hydrogenation of chloroacetophenone

In stainless steel clave, RuCl [(S, S)-T sdpen] (mesitylene) (1. 2 4 mg, 2 mo 1), Y b (〇T f) 3 (1. 2 4 mg, 2 mo 1),-chloroacetophe Non (0.3 g, 2 mm o 1) was charged and replaced with argon. After adding 4 ml of methanol and pressurizing with hydrogen, it was replaced 10 times. Hydrogen was charged up to 20 atm to start the reaction. After stirring at 30 ° C for 15 hours, the reaction pressure was returned to normal pressure. From ¹ HNMR and GC analysis of the product, 9 7% ee (R) -2-black-1 -phenylethanol was produced in 89% yield. Thus, a hydrogenation catalyst consisting of a chloride complex and Y b (OT f) ₃ is also useful for the asymmetric hydrogenation of hypochloroacetophenone. Note that RuCl [(S, S) -Tsdpen] (mesitylene) was synthesized according to the method described in the above-mentioned publicly known document, and a specific procedure is shown below. First, in a Schlenk-type reaction tube purged with argon, [R u C l ₂ (mesitylene)] ₂ (1.5 g, _2.5 mm o 1), (S, S)-T s DP EN U. 8 g , 5 mm o 1), triethylamine (1.4 ml, 10 mm o 1), and 2-propanol 30 m 1. Subsequently, the mixture was stirred at 80 for 1 hour. The solution was concentrated under reduced pressure (1 mmHg), and the precipitated crystals were collected by filtration and washed with 5 ml of water. Drying under reduced pressure (lm mH g) yielded 3 g of RuCl [(S, S) -T sdpen] (me sitylene).

[Examples 9-1 6]

Instead of Y b (OT f) ₃ , La (OT f) ₃ , P r (OT f) ₃ , G d (OT f) ₃ , Y (OT f) ₃ , S c (OT f) ₃ , B The reaction was carried out under the same conditions as in Example 8 except that (C ₆ F ₅ ) ₃ , Cu OT f, or In C l ₃ was used, and (R)-2-black mouth-1-phenyl Ethanol was synthesized. The results are summarized in Table 3. Thus, hydrogenation catalysts consisting of chloride complexes and various Lewis acids are also useful for the asymmetric hydrogenation reaction of chloroacetophenone. Table 3

Ru catalyst OH

Methanol Ph, Example Ru catalyst yield (%) ee (%)

9 RuCI [(S, S) -Tsdpen] (mesitylene), La (OTf) ₃ 83 97

10 RuCI [(S, S) -Tsdpen] (mesitylene), Pr (OTf) ₃ 81 97

11 RuCI [(S, S) -Tsdpen] (mesitylene), Gd (OTf) ₃ 79 97

12 RuCI [(S, S) -Tsdpen] (mesitylene), Y (OTf) ₃ 70 96

13 RuCI [(S, S) -Tsdpen] (mesitylene), Sc (OTf) ₃ 38 94

14 RuCI [(S, S) -Tsdpen] (mesitylene), B (C ₆ F ₅ ) ₃ 30 95

15 RuCI [(S, S) -Tsdpen] (mesitylene), CuOTf 44 96

16 RuCI [(S, S) -Tsdpen] (mesitylene), lnCI ₃ 25 95

Conditions: Ru cat 2 μηιοΙ, ketone / CH ₃ OH = 0.3 g / 4 ml, S / C = 1000, H ₂ 20 atm temp 30 ° C, time 15 h.

[Example 1 7]

The reaction was carried out under the same conditions as in Example 8 except that R u C l [(S, S) -T sdpen] (p—c ym ene) was used, and 95% ee (R) − 2-chloro- 1-phenylethanol was synthesized in a 76% yield. Thus, the hydrogenation catalyst in which the metal chloride complex is a p-cymene complex is also useful for the asymmetric hydrogenation of chloroacetophenone.

[Example 1 8]

Synthesis of (S)-4-chromanol by hydrogenation of 4- chromonone

In stainless steel clave, Ru [(S, S)-T sdpen] (p-c ym ene) (1.2 mg, 2 mol), Y b (OT f) ₃ (1. 8 6 mg, 3 mo 1), 4-Chromanone (0. 8 9 g, 6 mm o 1) was charged and the atmosphere was replaced with argon. Methanol 6 m I was added, pressurized with hydrogen, and replaced 10 times. Hydrogen was charged to 10 atm and the reaction was started. After stirring at 30 ° C. for 15 hours, the reaction pressure was returned to normal pressure. From iHNMR and HPLC analysis of the product, 96% ee (S) -4-chromanol was produced in 83% yield. The analysis results are as follows. ¹ HNMR (400 MHz, CDC 1 ₃ ) δ 1.99 (m, 1 H, C ϋΗ CHOH), 2.08 (m, 1 H, CHH.CHOH), 2.3 1 (br , 1 H, OH), 4. 2 3 (m, 2 H, CH ₂ OC), 4. 74 4 (m, 1 H, CHO H), 6. 8 1-6. 9 2 (m, 2 H , ar om atic H), 7. 1 7-7. 30 (m, 2 H, ar om atic H); HPLC (CH I RAL CELOJ-H; solvent, hexane Z 2 -propanol = 9 9 / 1; Flow rate, 1.5 ml / min; Temperature, 35 ° C; UV wavelength, 2 20 nm; (S)-4-Chromanol t _R , 2 6.7 min; (R)-4- Chromanol t _R , 3 0.8 min); Specific rotation [CK] ^{2 5} _D -7 2 ° (c 0.5, C ₂ H ₅ OH); Literature value, [H] ^{2 5} _D + 8 0 4 ° (c 0.5, C ₂ H ₅ OH), 100% ee (), J. Am. Chem. Soc. 1 993, 115, 3318.

[Comparative Example 1]

Stainless steel autoclave with Ru [(S, S)-T sdpen] (p-cyme ne) (1.2 mg, 2 mol), 4-Chromanon (0.30 g, 2 mm o 1) was charged and replaced with argon. Methanol 2 m 1 was added, pressurized with hydrogen, and replaced 10 times. Hydrogen was charged up to 30 atm and the reaction was started. After stirring at 50 ° C for 15 hours, the reaction pressure was returned to normal pressure. From ¹ HNMR and HPLC analysis of the product, 86% ee (S) -4-chromanol was produced in 7% yield. Thus, R u [(S, S)-T sdpen] (ρ-cy without adding Lewis acid If only mene) is used, the yield and optical purity are greatly reduced.

[Example 1 9-2 1]

Y b. The reaction was carried out under the same conditions as in Example 18 except that the amount of (OT f) ₃ was changed to synthesize (S) -4-chloroanol. The results are summarized in Table 4. Thus, a wide molar equivalent of Y b (OT f) · ₃ can be used for ruthenium.

Table 4

Example YbiOTf) ₃ / Ru yield (%) ee (%)

19 1.3 76 97

20 2.0 71 96 21 2.5 55 97

Conditions: Ru [(S, S) -Tsdpen] (p-cymene) 2 μιτιοΙ,

S / C = 3000, ketone / CH ₃ OH = 0.9 g / 6 ml, H ₂ 10 atm

temp 30 ° C, time 15h.

[Example 2 2-2 4]

(S) -4- chromanol was synthesized by carrying out the reaction under the same conditions as in Example 18 except that the substrate catalyst ratio and the amount of Y b (OT f) ₃ were changed. The results are summarized in Table 5. Table 5

ketone / Ch OH Yb (OTf) ₃ / Ru yield (%)

22 1500 0.44 g / 3 ml 1.0 100 96

23 5000 1.5 g / 10ml 1.5 42 96

24 5000 1.5 g / 10ml 2.5 48 96

Conditions: Ru [(S, S) -Tsdpen] (p-cymene) 2 μηηοΙ, H ₂ 10 atm, temp 30 ° C, time 15 h

[Example 2 5-2 6]

The reaction was carried out under the same conditions as in Example 18 except that the amount of solvent Y b (OT f) 3 was changed, and (S 4 -chromanol was synthesized. The results are summarized in Table 6. .

Table 6

Example ketone / CH ₃ OH Yb (OTf) ₃ / Ru yield (%) ee (%)

25 0.89 g / 12 ml 2.9 84 96

26 0.89 g / 3 ml 0.84 81 96

Conditions: Ru [(S, S) -Tsdpen] (p-cymene) 2 μηηοΙ, S / C = 3000

[Yb (OTf) ₃ ] ₀ = 0.45 mM, temp 30 ° C, time 15 h.

[Examples 2 7-2 9]

Use S c (OT f) ₃ instead of Y b (〇 T f) ₃ (S) -4- chromanol was synthesized by carrying out the reaction under the same conditions as in Example 18 except that was changed. The results are summarized in Table 7. Thus, a wide molar equivalent of S c (OT f) 3 can be used with respect to ruthenium.

Table 7

Example Sc (0Tf) ₃ / Ru yield (%) ee (%)

27 1.3 78 96

28 1.5 70 97

29 2.0 44 95

Conditions: Ru [(S, S) -1 sdpen] (p-cymene) 2 μιτιοΙ,

S / C = 3000, ketone / CH ₃ OH = 0.9 g / 6 ml, H ₂ 10 atm temp 30 ° C, time 15 h.

[Example 3 0-3 1]

Except that the substrate catalyst ratio, the amount of solvent, the amount of Y b (OT f) ₃ , the reaction temperature, and the hydrogen pressure were changed, the reaction was carried out under the same conditions as in Example 18 and (S)-4-chromanol was added. Synthesized. The results are summarized in Table 8.

Table 8

Example ketone / CH ₃ OH [Yb (OTf) ₃ ] (mM) yield (%) ee (%)

30 1.5 g / 0.5 ml 0.60 60 95

31 1.5 g / 0.7 ml 0.50 57 94

Conditions: Ru [(S, S) -Tsdpen] (p-cymene) 2 μηιοΙ, S / C = 5000

H ₂ 15 atm, temp 50 ° C, time 15 h.

[Example 3 2]

Synthesis of 2-chloro-1-(P-chlorophenyl) ethanol by hydrogenation of 2,4'-dichloroacetophenone

The reaction of 2,4'-dichloroacetophenone was carried out in the same manner as in Example 1. As a result of ¹ HNMR and GC analysis of the product, 9-% ee 2-chloro- 1-(p -chloro Mouthphenyl) Ethanol was produced in a yield of 100%. The analysis results are as follows. ¹ HNMR (400 MHz, CDC 1 ₃ ) S 2.88 (br, 1 H, OH), 3.5 8 (m, 1 H, C H_H CHOH), 3.68 (m, 1 H, C ΗΉ CHOH), 4.85 (m, 1 H, CHOH), 7. 26 (m, 4 H, aromatic H); GC (C hirasil-DEXCB; column temperature, 140 ° C) Injection temperature, 25 ° C .; detection temperature, 2 75; helium pressure, 100 k Pa; 2-chloro- 1- (p-black phenyl) t of the optical isomer of ethanol _R , 31.4 minutes, 34.7 minutes); (R, S not identified).

[Example 3 3]

m-1-(m-by hydrogenation of hydroxyacetophenone Hydroxyphenyl) Synthesis of ethanol

The reaction of m-hydroxyacetophenone was carried out in the same manner as in Example 1. From ¹ HNM R and GC analysis of the product, 95% ee of 1- (m-hydroxyphenyl) ethanol was 10%. It was produced in a yield of 0%. The analysis results are as follows. iHNMR. (4 0 0 MH z , acetone - d 6) <5 1 3 7 (d, J = 6 H z, 3 H, C H. 3), 4. 0 7 (d, J = 4 H z, 1 H, C HO L), 4. 7 7 (m, 1 H, CHOH), 6. 6 7-7.1 3 (m, 4 H, aromatic H), 8.1 5 (s, 1 H, OH); HPLC (CHI RA LCELOB; solvent, hexane / 2-propanol = 9 5 Z 5; flow rate, 1.0 ml / min; temperature, 35 ° C; UV wavelength, 25 4 nm; l- (m-Hydroxyphenyl) ether isomer t _R , 17.2 min, 31.5 min); (R, S not identified).

[Example 3 4]

1.- Synthesis of 1-indanol by hydrogenation reaction of indanone The reaction of 1-indanol was carried out in the same manner as in Example 1. From the ¹ HNM R and GC analysis of the product, 9 6% ee Of 1-indanol was produced in 95% yield. The analysis results are as follows.

MR (400 MHz, CDC 1 ₃ ) δ 1.92 (m, 1 H, C H_H C), 2.4 (s, 1 H, OH), 2.4 5 (m, 1 H , C HHO, 2.7 9 (m, 1 H, C ϋΗ CHOH), 3.0 3 (m, 1 H, C HH.CH〇H), 5. 2 0 (m, 1 H, C H_OH) , 7.2-7.40 (m, 4 H, aromatic H); HPLC (CHI RA LCEL ○ B-H; solvent, hexane / 2-propanol = 9/1; flow rate, 0.5 m 1 (Temperature, 3 5; UV wavelength, 2 5 4 nm; 't _R , 1 0.9 min, 1 6.0 min of the optical isomer of 1-indanol); (R and S have not been identified) Na I)

[Example 3 5]

4-Synthesis of 2-chloro-1-(p -methoxyphenyl) ethanol by hydrogenation of methoxyphenacyl chloride

The reaction of 4-methoxyphenacyl chloride was carried out in the same manner as in Example 1. As a result of ¹ HNMR and GC analysis of the product, 94% ee 2-black mouth-1-(p-meso Toxiphenyl) Ethanol was produced in a yield of 73%. The analysis results are as follows. ¹ HNMR (400 MHz, CD C 1 ₃ ) (5 3.3 6 (br, 1 H, CHOJi), 3.5 7-3.6 6 (m, ₂ ，, CH ₂ CHOH), 3.7 6 (s, 3 H, O CH ₃ ), 4.80 (m, 1 H, C Η, Ο H), 6.86 (d, J = 9 H z, 2 H, ar om atic H) , 7. 2 7 (d, J = 9 Hz, 2 H, ar om atic H); GC (C hirasil-D EX CB; column temperature, 140 ° C; injection temperature, 25 ° C; Detection temperature, 2 75 ° C; helium pressure, 100 k Pa; 2-black mouth-1-(P-methoxyphenyl) t _R of the optical isomer of ethanol, 3 0.1 (3, 1.7 minutes); (R and S are not identified).

[Example 3 6]

Preparation of catalyst obtained by mixing R u (OH) [(S, S)-T sdpen] (p-c yme ne) and Y b (〇T f) ₃

In an argon-substituted 20 m 1 Schlenk-type reaction tube, Ru [(S, S)-T sdpen] p-cyme ne) (1 6 6 mg, 0.28 mm o 1), THF 5 ml, Charged with lml water. After deaeration, the mixture was stirred at room temperature for 3 hours. Y b (OT f) 3 (17 2 mg, 0.28 mm o 1) (manufactured by A 1 drich) was added, and the mixture was further stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure (1 mmHg) and then dried to obtain 3 3 Omg of brown powder [Example 3 7]

Synthesis of (S)-4-chromanol by hydrogenation of 4-chromanone

A stainless steel clave was charged with the catalyst prepared in Example 36 (2.5 mg) and 4-chromanone (0.3 g, 2 mm o 1), and substituted with argon. Methanol 2 m 1 was added, pressurized with hydrogen, and then replaced 10 times. Hydrogen was charged to 30 atm to start the reaction. After stirring at 50 ° C. for 15 hours, the reaction pressure was returned to normal pressure. ¹ HNM R and HPLC analysis power of the product, 97% ee (S) -4-chromanol was produced in 99% yield.

[Example 3 8]

Synthesis of (S)-4-chromanol by hydrogenation of 4-chromanone

To the stainless steel autoclave, Ru H [(S, S)-T sdpen] (p-c ym ene (1.2 mg, 2 no 1;, Y b (OT f) 3 (0.6 3 mg , 1 mo 1), 4-Chromanone (0.3 g, 2 mm o 1) and purged with argon Methanol 2 m 1 was added, pressurized with hydrogen, and replaced 10 times. The reaction was started up to 0 atm and stirred for 15 hours at 50 ° C, and then the reaction pressure was returned to normal pressure From the ¹ HNM R and HPLC analysis of the product, 9 6% ee (S) -4-Chromaanol was produced in a yield of 100%.

In addition, RuH [(S, S) -Tsdpen] (p-cymene) was synthesized according to the method described in the above-mentioned publicly known document, and a specific procedure is shown below. First, Ru [(S, S)-T sdpen] (ρ-c ym ene) (1 3 0 mg, 0.2 2 mm o 1), 2-propanol 5 ml 1 was charged. Subsequently, after deaeration, the mixture was stirred at room temperature for 14 hours. 2-Propanol was distilled off under reduced pressure (1 mmHg), followed by drying to obtain RuH [(S, S) -Tsdpen] (p-cymene 13 mg).

[Example 3 9]

Synthesis of (R)-4-chromanol by hydrogenation of 4-chromanone

In stainless steel clave, Ru (CH ₂ N 0 ₂ ) [(R, R)-T sdpen] p-c ym ene) (1.3 mg, 2 mo 1), Y b (OT f) 3 (0.6 3 mg, 1 zmo 1) and 4-chromanone (0.3 g, 2 mm o 1) were charged, and the atmosphere was replaced with argon. Methanol 2 m 1 was added, pressurized with hydrogen, and replaced 10 times. Hydrogen was charged to 30 atm and the reaction was started. After stirring at 50 ° C. for 15 hours, the reaction pressure was returned to normal pressure. From ¹ H NMR and HPLC analysis of the product, 9 3% 6 6 (scale) -4- chromanol was produced in a 100% yield.

R u (CH 2 NO 2) [(R, R)-T sdpen] (ρ-cymene) was synthesized according to the method described in Organometallics Vol. 21, p253 (2002). The specific procedure is shown below. First, Ru [(R, R)-T sdpen] (p-c ym ene) (1 3 0 mg, 0.22 mm o 1), nitromethane (9 mg, 0.22 mm o 1) and 5 m 1 of methylene chloride were charged. Subsequently, after deaeration, the mixture was stirred at room temperature for 2 hours. Methylene chloride was distilled off under reduced pressure (I mmH g), and then dried, and R u (CH ₂ N 0 ₂ ) [(R, R)-T sdpen] (ρ-c ym ene) 1 4 0 mg was obtained.

[Example 4 0]

4-(R)-4-Chromanol by hydrogenation of chromonone Synthesis of

In stainless steel autoclave, C p * I r C l [(R, R)-T sdpen] (C p * represents pentamethylcyclopentene) (1.5 mg, 2 no 1), Y b (Ο Τ f) ₃ (0. 6 3 mg, 1 m ο 1), 4-Chromanone (0.3 g, 2 mm o 1), KO C (CH ₃ ) 3 (0. 2 2 mg, 2 xm ol) was charged and replaced with argon. After adding 2 ml of methanol and pressurizing with hydrogen, it was replaced 10 times. Hydrogen was charged to 30 atm and the reaction was started. After stirring at 50 ° C. for 15 hours, the reaction pressure was returned to normal pressure. From ¹ HNMR and HPLC analysis of the product, 96% ee (R) -4-chromanol was produced in 83% yield.

C p * I r C l [(R, R) -T sdpen] was synthesized in accordance with the method described in the above-mentioned publicly known document. The specific procedure is shown below. First, [C p * I r C l ₂ ] ₂ (6 60 mg, l mmo l), (R, R)-T s DPEN (8 0 0 mg, 2.2) mm o 1), triethylamine (0.6 m and 4.2 mm o 1), 2-propanol 30 m 1. Subsequently, the mixture was stirred at room temperature for 12 hours. The solution was concentrated to 10 m 1 under reduced pressure (1 mmHg), and the precipitated crystals were collected by filtration and washed with 5 m 1 of 2-propanol. Drying under reduced pressure (1 mmHg) yielded 1.2 g of Cp * IrCl [(R, R) -Tsdpen].

[Example 4 1]

Synthesis of (S) -4-chromanol by hydrogenation of 4-chromanone

To a stainless steel clave, C p * I r [(S, S)-T sdpen] (1.4 mg, 2 mo 1), Y b (OT f) ₃ (0. 6 3 mg, 1 mo 1), 4-chromanone (0.3 g, 2 mm o 1) was charged and purged with argon. Add 2 ml of methanol, pressurize with hydrogen, 1 Replaced 0 times. Hydrogen was charged to 30 atm to start the reaction. After stirring at 50 ° C. for 15 hours, the reaction pressure was returned to normal pressure. From ¹ HNMR and HP LC analysis of the product, 92% ee (S) -4-chromanol was produced in a 100% yield.

Cp * Ir [(S, S) -Tsdpen] was synthesized in accordance with the method described in the above-mentioned publicly known document. The specific procedure is shown below. First, C p * I r C 1 [(S, S)-T sdpen] (2 1 m, 0. 0 3 2 mmo l), 0.1 MN a OH aq (3 2 1, 0. 0 3 2mmol) and methylene chloride 5 ml 1 were charged. Subsequently, the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure (I mmH g), followed by drying to obtain C p * I r [(S, S) -T s d pen] 22 mg. Industrial applicability

The present invention is used to produce optically active alcohols as pharmaceuticals, agricultural chemicals, or synthetic intermediates of many general-purpose chemicals.

Claims

The scope of the claims

1. a group 8 or group 9 transition metal complex with a metal amide bond;

A hydrogenation catalyst containing Lewis acid (excluding Brenstead acid that releases protons) and

2. A hydrogenation catalyst obtained by premixing a group 8 or group 9 transition metal complex having a metal amide bond and a Lewis acid (excluding Brenstead acid releasing a peptone).

3. Group 8 or group 9 transition metal complexes with amine ligands,

A hydrogenation catalyst containing Lewis acid (excluding Brenstead acid that releases proton) and

4. A hydrogenation catalyst obtained by premixing a Group 8 or Group 9 transition metal complex having an amine ligand and a Lewis acid (excluding Brenstead acid that releases proton).

5. The hydrogenation catalyst according to claim 1 or 2, wherein the group 8 or group 9 transition metal complex having a metal amide bond is a compound represented by the general formula (1). General formula (1)

(In the general formula (1), R ¹ and R ² may be the same or different from each other, and may have a substituent, an alkyl group, a phenyl group, a naphthyl group, or a cycloalkyl group. Or a part of the ring when bonded to each other to form an alicyclic ring,

R ³ may have a substituent, an alkyl group, a naphthyl group, Nil group or force

R ⁴ is a hydrogen atom or an alkyl group,

Ar is bonded to M ¹ via a 7T bond, benzene which may have a substituent or a pentapentenyl group which may have a substituent,

M ¹ is ruthenium, rhodium or iridium,

* Indicates an asymmetric carbon. )

6. In the general formula (1), R ¹ and R ² may be the same or different from each other, a phenyl group, a phenyl group having an alkyl group having 1 to 5 carbon atoms, and a carbon number The phenyl group having 1 to 5 alkoxy groups or the phenyl group having a halogen substituent, or an alkyl group which may be bonded to each other to form a 5-membered ring or a 6-membered ring. Hydrogenation catalyst.

7. The hydrogenation catalyst according to claim 3 or 4, wherein the group 8 or group 9 transition metal complex having an amine ligand is a compound represented by the general formula (2). General formula (2)

(In the general formula (2), R ¹ and R ² may be the same or different from each other, and may have a substituent, an alkyl group, a phenyl group, a naphthyl group, or a cycloalkyl group. Or a part of the ring when bonded to each other to form an alicyclic ring,

R ³ is an alkyl group, a naphthyl group, a phenyl group or a camphor which may have a substituent,

R ⁴ is a hydrogen atom or an alkyl group, Ar is an optionally substituted benzene bonded to M ¹ through a 兀 bond, or an optionally substituted pentenyl group.

M ¹ is ruthenium, rhodium or iridium,

* Indicates an asymmetric carbon. )

8. In the general formula (2), R ¹ and R ² may be the same or different from each other, a phenyl group, a phenyl group having an alkyl group having 1 to 5 carbon atoms, and a carbon number The phenyl group having 1 to 5 alkoxy groups or the phenyl group having a halogen substituent, or an alkyl group which may be bonded to each other to form a 5-membered ring or a 6-membered ring. Hydrogenation catalyst.

9. The hydrogenation catalyst according to any one of claims 5 to 8, wherein the Lewis acid is a compound represented by the general formula (3).

General formula (3)

M ² _m X ² _n

(In the general formula (3), M ² is boron, aluminum, silicon, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, niger, copper, zinc, gallium, germanium, yttrium, zirconium. , Niobium, molybdenum, technetium, ruthenium, rhodium, paradium, silver, cadmium, indium, tin, antimony, lanthanum, cerium, prasedium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, dysprosium, Thulium, Ytterbium, Lutetium, Hafnium, Tantalum, Tungsten, Rhenium, Osmium, Iridium, Platinum, Gold, Mercury, Thallium, Lead, Bismuth or Actinoide M is an integer of 1 or 2,

X ² may be the same or different from each other, an anionic group, An alkyl group, or an optionally substituted phenyl group, and n represents an integer of 2 to 14. )

10. A process for producing an alcohol compound, wherein a ketone compound is hydrogenated with a hydrogenation catalyst according to any one of claims 1 to 9 to obtain an alcohol compound in the presence of hydrogen or a compound that donates hydrogen.

1 1. In the presence of hydrogen or a compound that donates hydrogen, the hydrogenation catalyst according to any one of claims 5 to 9, wherein the asymmetric carbons are all in R form or both in S form. A method for producing an alcohol compound, wherein a ketone compound is hydrogenated to obtain an optically active alcohol compound.

1 2. The method for producing an alcohol compound according to claim 10 or 11, wherein the ketone compound is hydrogenated using one or more selected from the group consisting of methanol, ethanol and 2-propanol as a solvent.