JP4713134B2 - Process for producing optically active alkylphthalides - Google Patents

Description

  The present invention relates to a method for producing optically active alkylphthalides used as pharmaceutical intermediates, liquid crystal materials or cosmetics.

Methods for producing optically active lactones include (i) a method using an optically active natural product as a starting material (Non-patent Document 1), and (ii) a method of synthesizing by reduction of γ-keto acid by yeast (non-patent). Documents 2), (iii) a method of optically resolving a racemate (Patent Document 1), (iv) a method of reducing a γ-ketoester with an optically active ruthenium phosphine complex (Patent Document 2), and the like are known.
However, the method of using the natural product (i) as a starting material has many steps and is complicated. The microorganism-based method (ii) has not yet been obtained with a high optical purity. The method (iii) by optical resolution requires an equivalent amount of an optically active substance, has poor resolution efficiency, and the aliphatic γ-ketoester (vi) has high optical purity, but is aromatic. In the hydrogenation of the ketone located next to the ring, there is a problem that a high optical purity is not yet obtained.
Furthermore, there has been no report on a method for synthesizing optically active alkylphthalides among optically active lactones.
JP 55-43053 A JP-A-4-108782 Agric. Biol. Chem. 51, 635 (1987) Appl. Microbiol. 11, 389 (1963)

  An object of the present invention is to provide a synthesis method capable of obtaining optically active alkyl phthalides which are simple, have a small number of steps, and have good optical purity.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the target compound can be produced in a short process and with good yield and optical purity by passing an alkylidene phthalide as an intermediate, The present invention has been completed.

  That is, the present invention provides the following general formula (3):

(In the formula, ring A represents an optionally substituted aromatic ring; X and X ′ each independently represents a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen-substituted alkylsulfonyloxy group. Show)
A phthalic acid derivative represented by the following general formula (4):

(In the formula, Y represents a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen-substituted alkylsulfonyloxy group: l represents an integer of 2 to 8)
Is reacted with a magnesium compound represented by the following general formula (2):

(Wherein, rings A and l are as defined above; the wavy line indicates a double bond cis-form and / or trans-form)
General formula (1) characterized in that an alkylidenephthalide represented by the following formula is obtained and then asymmetrically hydrogenated:

(In the formula, rings A and l are as defined above; * indicates an asymmetric carbon atom)
The manufacturing method of optically active alkylphthalides represented by these is provided.

  The present invention also provides the following general formula (3):

(In the formula, ring A represents an optionally substituted aromatic ring; X and X ′ each independently represents a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen-substituted alkylsulfonyloxy group. Show)
A phthalic acid derivative represented by the following general formula (4):

(Wherein Y represents a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group or a halogen-substituted alkylsulfonyloxy group; l represents an integer of 2 to 8)
The following general formula (2) characterized by reacting with a magnesium compound represented by the formula:

(Wherein, rings A and l are as defined above; the wavy line indicates a double bond cis-form and / or trans-form)
The manufacturing method of alkylidene phthalides represented by these is provided.

  The present invention also provides the following general formula (2):

(In the formula, ring A represents an aromatic ring which may have a substituent; l represents an integer of 2 to 8; a wavy line represents a cis-form and / or a trans-form of a double bond. )
Wherein the alkylidenephthalide represented by the general formula (1) is asymmetrically hydrogenated:

(In the formula, rings A and l are as defined above; * indicates an asymmetric carbon atom)
The manufacturing method of optically active alkylphthalides represented by these is provided.

  The present invention is a process for producing optically active alkylphthalides important as various pharmaceutical intermediates, liquid crystal materials or cosmetics in a simple manner with a small number of steps and with high optical purity, and is industrially advantageous. .

  The method for producing the optically active alkylphthalide of the present invention is carried out according to the reaction shown below.

(In the formula, ring A represents an optionally substituted aromatic ring; X and X ′ each independently represents a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen-substituted alkylsulfonyloxy group. X represents a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group or a halogen-substituted alkylsulfonyloxy group; a wavy line represents a double bond cis-form and / or trans-form; l represents an integer of 2 to 8; * Indicates an asymmetric carbon atom)

  That is, an alkylidenephthalide (2) is obtained by reacting the phthalic acid derivative (3) with the magnesium compound (4), and then optically active alkylphthalide (1) is obtained by asymmetric hydrogenation.

  Ring A in the phthalic acid derivative of the general formula (3), the alkylidene phthalides of the general formula (2), and the optically active alkyl phthalide of the general formula (1) of the present invention may have a substituent. It is a family ring. Specific examples of the aromatic ring of ring A include, for example, hydrocarbon-based aromatic rings such as a benzene ring, naphthalene ring, and phenanthrene ring; pyrrole ring, pyridine ring, pyrazine ring, quinoline ring, isoquinoline ring, imidazole ring, Heteroaromatic rings; metallocene aromatic rings such as ferrocene ring and titanocene ring.

  Here, specific examples of the substituent include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, C1-C12 alkyl groups such as isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group; methoxy group, ethoxy group, n-propoxy group, isopropoxy group Group, lower alkoxy group having 1 to 4 carbon atoms such as n-butoxy group, isobutoxy group, sec-butoxy group and tert-butoxy group; aryl group such as phenyl group, α-naphthyl group, β-naphthyl group and phenanthryl group Benzyl group, α-phenylethyl group, β-phenylethyl group, α-phenylpropyl group, β-phenylpropyl group, γ- Aralkyl groups having 7 to 13 carbon atoms such as an phenylpropyl group and a naphthylmethyl group; a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a diethylisopropylsilyl group, dimethyl (2,3-dimethyl-2- Butyl) silyl group, tert-butyldimethylsilyl group, dimethylhexylsilyl group, etc., tri-C1-C6 alkylsilyl group, dimethylcumylsilyl group, etc., di-C1-6 alkyl-C6-C18 Di-C6-C18 aryl-C1-C6 alkylsilyl group such as arylsilyl group, tert-butyldiphenylsilyl group, diphenylmethylsilyl group, Tri-C6-C18 arylsilyl such as triphenylsilyl group Group, tribenzylsilyl group, tri-p-xylylsilyl group, etc. -Tri-substituted organosilyl groups such as C7-19 aralkylsilyl groups; halogen atoms such as fluorine, chlorine, bromine and iodine; nitro groups and the like.

  Preferred ring A includes a benzene ring.

  In the phthalic acid derivative of the general formula (3) of the present invention, X and X ′ are each independently a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group or a halogen-substituted alkylsulfonyloxy group.

  Specific examples of X and X ′ include, for example, halogen atoms such as fluorine, chlorine, bromine and iodine; alkylsulfonyloxy groups such as methanesulfonyloxy group, ethanesulfonyloxy group and camphilsulfonyloxy group; benzenesulfonyloxy group Arylsulfonyloxy groups such as p-toluenesulfonyloxy group, p-chlorophenylsulfonyloxy group and naphthylsulfonyloxy group; halogen-substituted alkylsulfonyloxy groups such as trifluoromethanesulfonyloxy group and trichloromethanesulfonyloxy group.

  In the magnesium compound of the general formula (4) of the present invention, Y is a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen-substituted alkylsulfonyloxy group.

  Specific examples of Y include, for example, halogen atoms such as fluorine, chlorine, bromine and iodine; alkylsulfonyloxy groups such as methanesulfonyloxy group, ethanesulfonyloxy group and camphilsulfonyloxy group; benzenesulfonyloxy group, p- Examples include arylsulfonyloxy groups such as toluenesulfonyloxy group, p-chlorophenylsulfonyloxy group, and naphthylsulfonyloxy group; halogen-substituted alkylsulfonyloxy groups such as trifluoromethanesulfonyloxy group and trichloromethanesulfonyloxy group.

  Examples of the magnesium compound of the general formula (4) include propyl magnesium fluoride (n = 1), butyl magnesium fluoride (n = 2), pentyl magnesium fluoride (n = 3), hexyl magnesium fluoride (n = 4), heptylmagnesium fluoride (n = 5), octylmagnesium fluoride (n = 6), nonylmagnesium fluoride (n = 7), decylmagnesium fluoride (n = 8); propylmagnesium chloride, butylmagnesium chloride , Pentylmagnesium chloride, hexylmagnesium chloride, heptylmagnesium chloride, octylmagnesium chloride, nonylmagnesium chloride, decylmagnesium chloride; propylmagnesium bromide, butylmagnesium bromide, pentylmagnesium Mubromide, hexylmagnesium bromide, heptylmagnesium bromide, octylmagnesium bromide, nonylmagnesium bromide, decylmagnesium bromide; propylmagnesium iodide, butylmagnesium iodide, pentylmagnesium iodide, hexylmagnesium iodide, heptylmagnesium iodide, octylmagnesium Iodide, nonylmagnesium iodide, decylmagnesium iodide; propylmagnesium methanesulfonate, butylmagnesium methanesulfonate, pentylmagnesium methanesulfonate, hexylmagnesium methanesulfonate, heptylmagnesium methanesulfonate, octylmagnesium methanesulfonate, nonyl Magnesium methanesulfonate Decylmagnesium methanesulfonate; propylmagnesiumbenzenesulfonate, butylmagnesiumbenzenesulfonate, pentylmagnesiumbenzenesulfonate, hexylmagnesiumbenzenesulfonate, heptylmagnesiumbenzenesulfonate, octylmagnesiumbenzenesulfonate, nonylmagnesiumbenzenesulfonate, decylmagnesium Benzene sulfonate; propyl magnesium p-toluene sulfonate, butyl magnesium p-toluene sulfonate, pentyl magnesium p-toluene sulfonate, hexyl magnesium p-toluene sulfonate, heptyl magnesium p-toluene sulfonate, octyl magnesium p-toluene sulfo Nato, nonylmagnesium p-tolue Sulfonate, decylmagnesium p-toluenesulfonate; propylmagnesium trifluoromethanesulfonate, butylmagnesium trifluoromethanesulfonate, pentylmagnesium trifluoromethanesulfonate, hexylmagnesium trifluoromethanesulfonate, heptylmagnesium trifluoromethanesulfonate, octylmagnesium trifluoromethanesulfone Nalto, nonylmagnesium trifluoromethanesulfonate, decylmagnesium trifluoromethanesulfonate, and the like.

  Preferred magnesium compounds of the general formula (4) include propyl magnesium fluoride (n = 1), butyl magnesium fluoride (n = 2), pentyl magnesium fluoride (n = 3), hexyl magnesium fluoride (n = 4). ), Heptylmagnesium fluoride (n = 5), octylmagnesium fluoride (n = 6), nonylmagnesium fluoride (n = 7), decylmagnesium fluoride (n = 8); propylmagnesium chloride, butylmagnesium chloride, Pentylmagnesium chloride, hexylmagnesium chloride, heptylmagnesium chloride, octylmagnesium chloride, nonylmagnesium chloride, decylmagnesium chloride; propylmagnesium bromide, butylmagnesium bromide, pentylmagnesium Mubromide, hexylmagnesium bromide, heptylmagnesium bromide, octylmagnesium bromide, nonylmagnesium bromide, decylmagnesium bromide; propylmagnesium iodide, butylmagnesium iodide, pentylmagnesium iodide, hexylmagnesium iodide, heptylmagnesium iodide, octylmagnesium Examples thereof include iodide, nonylmagnesium iodide, decylmagnesium iodide and the like.

  The production method of the magnesium compound (4) is not particularly limited. A. Shirley; Org. React. , Vol. 8, pp. 28-58 (1954) or a method analogous thereto. Moreover, you may use a commercial item.

  These magnesium compounds may be used singly or in appropriate combination of two or more in the same l range.

  Although it does not restrict | limit especially as a manufacturing method of the phthalic acid derivative of General formula (3), For example, it can manufacture by the method as described in Unexamined-Japanese-Patent No. 47-27949, Unexamined-Japanese-Patent No. 56-103131, or a method similar to this. it can. Moreover, you may use a commercial item.

Below, the manufacturing method of this invention is demonstrated more concretely.
In order to carry out the production method of the present invention, a phthalic acid derivative of the general formula (3) and a magnesium compound of the general formula (4) are carbon-carbon in an organic solvent in an inert gas atmosphere such as argon or nitrogen. An optically active alkylphthalide of the general formula (1) can be produced by performing a coupling reaction to produce alkylidenephthalides (2) and then asymmetric hydrogenation.

  In the carbon-carbon bond reaction between the phthalic acid derivative (3) and the magnesium compound (4), (i) a solution obtained by dissolving the phthalic acid derivative (3) in an organic solvent and a magnesium compound (4) in the organic solvent. A method in which a dissolved or suspended solution is dropped to cause a carbon-carbon bond reaction, (b) a solution in which a magnesium compound (4) is dissolved or suspended in an organic solvent, and a phthalic acid derivative (3) in an organic solvent A method in which the dissolved solution is dropped to cause a carbon-carbon bond reaction is employed, and the method (a) is preferably employed.

  The reaction ratio between the phthalic acid derivative and the magnesium compound (4) is preferably about 1 to 8 mol of the magnesium compound (4) with respect to 1 mol of the phthalic acid derivative (3). More preferably, it is about 1.5 mol.

  Specific examples of the magnesium compound include the compounds described above, and one or more of these compounds can be used within the same range of l.

  As the organic solvent, an organic solvent that does not adversely affect the carbon-carbon bond reaction between the phthalic acid derivative (3) and the magnesium compound (4) is used. For example, hydrocarbon solvents such as pentane, hexane, and heptane, cyclohexane , Alicyclic hydrocarbon solvents such as methylcyclohexane and decalin, aromatic solvents such as benzene, toluene and xylene, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, 1,3-dioxolane and dioxane Etc., and one or more of them can be used. Among these, tetrahydrofuran and / or toluene are preferably used because they have good operability and are economically inexpensive. Usually, the amount of the organic solvent used is preferably about 0.5 to 20 times by volume, more preferably about 1 to 10 times by volume, relative to 1 part by mass of the phthalic acid derivative (3). preferable.

  In performing a carbon-carbon bond reaction by dropping a solution obtained by dissolving or suspending a magnesium compound (4) in an organic solvent into a solution obtained by dissolving the phthalic acid derivative (3) in an organic solvent, a magnesium compound is used. The dropping time of the solution obtained by dissolving (4) in an organic solvent is usually preferably about 1 to 180 minutes, more preferably about 5 to 60 minutes. The reaction temperature is preferably about −80 to 50 ° C., more preferably about −50 to 10 ° C., and after completion of the dropwise addition of the solution in which the magnesium compound (4) is dissolved in the organic solvent while maintaining the temperature. The alkylidenephthalides (2) can be produced smoothly by reacting for about 0.5 to 15 hours, preferably about 1 to 5 hours.

The alkylidenephthalides (2) obtained by the carbon-carbon bond reaction described above are oily and can be stored. Therefore, the alkylidene phthalides (2) obtained by the above reaction are purified by, for example, distillation or column chromatography, or stored without performing purification, and optically active alkyl phthalides (1 ) May be taken out from the storage container at the time of production.
The aforementioned alkylidenephthalides (2) are a mixture of (E) -form and (Z) -form, and when used for asymmetric hydrogenation in the next step, (E) -form and (Z) -form It is also possible to separate and purify the mixture with In addition, when the obtained alkylidenephthalides (2) have a higher sterically more stable (Z) -isomer ratio, the (E) -isomer and the (Z) -isomer are separated and purified. Instead, the mixture may be used for asymmetric hydrogenation in the next step.

Optically active alkyl phthalides (1) are produced by asymmetric hydrogenation of alkylidene phthalides (2) obtained by the carbon-carbon bond reaction described above.
The method for asymmetric hydrogenation of alkylidenephthalides (2) is not particularly limited. For example, (a) a method of reducing by hydrogenation using an optically active transition metal complex as a catalyst, and (b) reduction by a microorganism such as yeast. And (c) a method of reducing with an optically active metal halide. Preferably, (a) a method of reducing by hydrogenation using an optically active transition metal complex as a catalyst is employed.

  The optically active transition metal complex used in the present invention is preferably a complex containing a transition metal complex and a ligand, and the ligand is more preferably an optically active substance. The component may be an optically active substance.

  Examples of the ligand used in the optically active transition metal complex for asymmetric hydrogenation of the alkylidenephthalides (2) of the present invention include monodentate ligands and multidentate ligands. An optically active bidentate phosphine ligand is preferable.

As an optically active bidentate phosphine ligand, the following general formula (7) :

(In the formula, R ^{1 to} R ⁴ each independently represents an aromatic group which may have a substituent or a cycloalkyl group having 3 to 10 carbon atoms, or R ¹ and R ² , R ³ and R ⁴ may each form a heterocyclic ring together with adjacent phosphorus atoms; R ⁵ and R ⁶ each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms. alkoxy group, diamino group (containing 1-5 alkyl carbon atoms), shows a 5-8 membered cyclic amino group or a halogen atom; R ⁷ is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, A di (C 1-5 alkyl) amino group, a 5- to 8-membered cyclic amino group or a halogen atom; and R ⁵ and R ⁶ , R ⁶ and R ⁷ , together, are condensed benzene Ring, condensed substituted benzene ring, trimethylene group, tetramethylene group, pentamethylene group, methylene Oxy group, may form an ethylenedioxy group or a trimethylenedioxy group)
The optically active bidentate phosphine ligand represented by these is mentioned.

In the general formula (7), R ^{1 to} R ⁴ each independently represent an optionally substituted aromatic group or a cycloalkyl group having 3 to 10 carbon atoms, or R ¹ and R ² , R ³ and R ⁴ may form a heterocyclic ring together with adjacent phosphorus atoms.

  In the aromatic group which may have a substituent, the aromatic group includes hydrocarbon aromatic groups such as phenyl group, naphthyl group, phenanthryl group; pyrrolyl group, pyridyl group, pyrazyl group, quinolyl group, isoquinolyl group And heteroaromatic groups such as an imidazolyl group.

  Here, specific examples of the substituent include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, and isopentyl. Group, neopentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group and other alkyl groups having 1 to 12 carbon atoms; methoxy group, ethoxy group, n-propoxy group, isopropoxy group N-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group and the like lower alkoxy group having 1 to 4 carbon atoms; phenyl group, α-naphthyl group, β-naphthyl group, fananthryl group and the like aryl group Benzyl group, α-phenylethyl group, β-phenylethyl group, α-phenylpropyl group, β-phenylpropyl group, γ-phenyl group; Aralkyl groups having 7 to 13 carbon atoms such as nylpropyl group and naphthylmethyl group; trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, diethylisopropylsilyl group, dimethyl (2,3-dimethyl-2-butyl) ) Tri-C1-C6 alkylsilyl group such as silyl group, tert-butyldimethylsilyl group, dimethylhexylsilyl group, etc. Di-C1-C6 alkyl-C6-C18 aryl such as dimethylcumylsilyl group Di-C6-C18 aryl-C1-C6 alkylsilyl group such as silyl group, tert-butyldiphenylsilyl group, diphenylmethylsilyl group, Tri-C6-C18 arylsilyl group such as triphenylsilyl group , Tribenzylsilyl group, tri-p-xylylsilyl group, etc. -Tri-substituted organosilyl groups such as C7-19 aralkylsilyl groups; halogen atoms such as fluorine, chlorine, bromine and iodine; nitro groups and the like.

  In the cycloalkyl group having 3 to 10 carbon atoms which may have a substituent, specific examples of the cycloalkyl group include a cyclopentyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, A cyclononyl group, a cyclodecyl group, an octahydronaphthyl group, etc. are mentioned.

  Here, specific examples of the substituent include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, C1-C12 alkyl groups such as isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group; methoxy group, ethoxy group, n-propoxy group, isopropoxy group Group, lower alkoxy group having 1 to 4 carbon atoms such as n-butoxy group, isobutoxy group, sec-butoxy group and tert-butoxy group; aryl such as phenyl group, α-naphthyl group, β-naphthyl group and fananthryl group Group: benzyl group, α-phenylethyl group, β-phenylethyl group, α-phenylpropyl group, β-phenylpropyl group, γ- Aralkyl groups having 7 to 13 carbon atoms such as an phenylpropyl group and a naphthylmethyl group; a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a diethylisopropylsilyl group, dimethyl (2,3-dimethyl-2- Butyl) silyl group, tert-butyldimethylsilyl group, dimethylhexylsilyl group, etc., tri-C1-C6 alkylsilyl group, dimethylcumylsilyl group, etc., di-C1-6 alkyl-C6-C18 Di-C6-C18 aryl-C1-C6 alkylsilyl group such as arylsilyl group, tert-butyldiphenylsilyl group, diphenylmethylsilyl group, Tri-C6-C18 arylsilyl such as triphenylsilyl group Group, tribenzylsilyl group, tri-p-xylylsilyl group, etc. Examples include tri-substituted organosilyl groups such as a tri-carbon number of 7 to 19 aralkylsilyl groups; halogen atoms such as fluorine, chlorine, bromine and iodine; nitro groups and the like.

Specific examples of the heterocyclic ring in the case where R ¹ and R ² , R ³ and R ⁴ are combined with adjacent phosphorus atoms to form a heterocyclic ring include phosphole, tetrahydrophosphole, and phosphorinan. The heterocyclic ring may have 1 to 4 functional groups inert to the reaction of the present invention as a substituent. Examples of the substituent include an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and a halogen atom.

In the general formula (7), R ⁵ and R ⁶ are each independently a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a di (1 to 5 alkyl) amino group, 5 It is a ˜8-membered cyclic amino group or a halogen atom.

Specific examples of the alkyl group having 1 to 5 carbon atoms represented by R ⁵ and R ⁶ include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl. Group, tert-butyl group, pentyl group and the like.

Specific examples of the alkoxy group having 1 to 5 carbon atoms represented by R ⁵ and R ⁶ include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec- Examples include butoxy group, tert-butoxy group, pentoxy group and the like.

Specific examples of the di (C 1-5 alkyl) amino group represented by R ⁵ and R ⁶ include a dimethylamino group, a diethylamino group, a di-n-propylamino group, a diisopropylamino group, and di-n-butyl. Examples thereof include an amino group, a diisobutylamino group, a disec-butylamino group, a ditert-butylamino group, and a dipentylamino group.

Specific examples of the 5- to 8-membered cyclic amino group represented by R ⁵ and R ⁶ include a pyrrolidino group and a piperidino group.

Specific examples of the halogen atom represented by R ⁵ and R ⁶ include fluorine, chlorine, bromine, iodine and the like.

Among these, preferable R ⁵ and R ⁶ include a hydrogen atom; a carbon number of 1 to 4 such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, and a trifluoromethyl group. Alkoxy groups: alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy group; dimethylamino group, dialkylamino group of diethylamino group; pyrrolidino group, piperidino group, etc. And a 5- to 8-membered cyclic amino group.
Particularly preferred examples of R ⁵ and R ⁶ include a hydrogen atom and a methoxy group.

In the general formula (7), each R ⁷ is independently an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a di (1 to 5 alkyl) amino group, or a 5- to 8-membered cyclic amino group. A group or a halogen atom.

Specific examples of the alkyl group having 1 to 5 carbon atoms represented by R ⁷ include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert. -A butyl group, a pentyl group, etc. are mentioned.

Specific examples of the alkoxy group having 1 to 5 carbon atoms represented by R ⁷ include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, Examples thereof include a tert-butoxy group and a pentoxy group.

Specific examples of the di (C 1-5 alkyl) amino group represented by R ⁷ include a dimethylamino group, a diethylamino group, a di-n-propylamino group, a diisopropylamino group, a di-n-butylamino group, Examples thereof include a diisobutylamino group, a disec-butylamino group, a ditert-butylamino group, and a dipentylamino group.

Specific examples of the 5- to 8-membered cyclic amino group represented by R ⁷ include a pyrrolidino group and a piperidino group.

Specific examples of the halogen atom represented by R ⁷ include fluorine, chlorine, bromine, iodine and the like.

Among these, preferred R ⁷ is an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a tert-butyl group or a trifluoromethyl group; a methoxy group Alkoxy groups such as ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group and tert-butoxy group; dialkylamino groups such as dimethylamino group and diethylamino group; 5- to 8-members such as pyrrolidino group and piperidino group And the like, and the like.
Particularly preferred R ⁷ includes a methyl group and a methoxy group.

In the general formula (7), R ⁵ and R ⁶ , R ⁶ and R ⁷ are combined together to form a condensed benzene ring, a condensed substituted benzene ring, a trimethylene group, a tetramethylene group, a pentamethylene group, a methylenedioxy group, An ethylenedioxy group or a trimethylenedioxy group may be formed. Among these, R ⁶ and R ⁷ together form a condensed benzene ring, a condensed substituted benzene ring, a trimethylene group, a tetramethylene group, a pentamethylene group, a methylenedioxy group, an ethylenedioxy group, or a trimethylenedioxy group. What formed is preferable. In particular, R ⁶ and R ⁷ are preferably combined to form a condensed benzene ring, a condensed substituted benzene ring, a tetramethylene group, a methylenedioxy group, a methylenedioxy group, or an ethylenedioxy group.

  In addition, the condensed benzene ring, condensed substituted benzene ring, trimethylene group, tetramethylene group, pentamethylene group, methylenedioxy group, ethylenedioxy group or trimethylenedioxy group have functional groups that are inert to the asymmetric synthesis reaction. The group may be substituted in a range of preferably 0 to 4 groups. Here, examples of the substituent include alkyl having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Group: hydroxyl group; alkoxy group having 1 to 4 carbon atoms such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group; fluorine, chlorine , Halogen atoms such as bromine and iodine.

  Examples of the optically active bidentate phosphine ligand preferably used in the general formula (7) include tertiary phosphines described in JP-A-61-63690 and JP-A-62-265293. Specific examples include the following. That is, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 2,2′-bis (di (p-tolylphosphino) -1,1′-binaphthyl [p-Tol-BINAP] 2,2′-bis (di (3,5-xylyl) phosphino) -1,1′-binaphthyl (DM-BINAP), 2,2′-bisdi (3,5-di-tert-butylphenyl) ) Phosphino) -1,1′-binaphthyl (T-Bu-2-BINAP), 2,2′-bis [di (4-methoxy-3,5-dimethylphenyl) phosphino] -1,1′-binaphthyl ( DMM-BINAP), 2,2′-bis (dicyclohexylphosphino) -1,1′-binaphthyl (Cy-BINAP), 2,2′-bis (dicyclopentylphosphino) -1,1′-binaphthyl (Cp) -BINAP).

Furthermore, in this general formula (7), the optically active bidentate phosphine ligand preferably used is, for example, a tertiary phosphine described in JP-A-4-139140. Things can be mentioned. That is, 2,2′-bis (diphenylphosphino) -5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydrobinaphthyl (H ₈ -BINAP), 2,2′-bis (Di-p-tolylphosphino) -5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydrobinaphthyl (p-Tol-H ₈ -BINAP), 2,2′-bis (G (3,5-xylyl) phosphino) -5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydrobinaphthyl (DM-H ₈ -BINAP), 2,2′-bis (G (4-Methoxy-3,5-dimethylphenyl) phosphino) -5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydrobinaphthyl (DMM-H ₈ -BINAP).

  Furthermore, in this general formula (7), the optically active bidentate phosphine ligand preferably used is, for example, a tertiary phosphine described in JP-A No. 11-269185. As a specific example, The following can be mentioned. That is, ((5,6), (5 ′, 6 ′)-bis (methylenedioxy) biphenyl-2,2′-diyl) bis (diphenylphosphine) (SEGPHOS), ((5,6), (5 ', 6')-bis (methylenedioxy) biphenyl-2,2'-diyl) bis (di-p-tolylphosphine) (p-Tol-SEGPHOS), ((5,6), (5 ', 6' ) -Bis (methylenedioxy) biphenyl-2,2′-diyl) bis (di3,5-xylylphosphine) (DM-SEGPHOS), ((5,6), (5 ′, 6 ′)-bis (Methylenedioxy) biphenyl-2,2′-diyl) bis (di-4-methoxy-3,5-dimethylphenylphosphine) (DMM-SEGPHOS), ((5,6), (5 ′, 6 ′)- Bis (methylenedioxy) biphenyl-2,2 -Diyl) bis (di-4-methoxy-3,5-di-tert-butylphenylphosphine) (DTBM-SEGPHOS), ((5,6), (5 ', 6')-bis (methylenedioxy) biphenyl -2,2'-diyl) bis (dicyclohexylphosphine) (Cy-SEGPHOS).

  In addition to the above optically active bidentate phosphine ligands, the following optically active bidentate phosphine ligands can be exemplified as those corresponding to the general formula (7). That is, 2,2′-dimethyl-6,6′-bis (diphenylphosphino) -1,1′-biphenyl (BIPHEMP), 2,2′-dimethyl-6,6′-bis (di-p-tolylphosphino) -1,1′-biphenyl (p-Tol-BIPHEMP), 2,2′-dimethyl-6,6′-bis (di3,5-xylylphosphino) -1,1′-biphenyl (DM-BIPHEMP) ), 2,2′-dimethyl-6,6′-bis (di-4-methoxy-3,5-dimethylphenylphosphino) -1,1′-biphenyl (DMM-BIPHEMP), 2,2′-dimethyl- 6,6′-bis (di-4-tert-butoxy-3,5-dimethylphenylphosphino) -1,1′-biphenyl (DTBM-BIPHEMP), 2,2′-dimethyl-6,6′-bis ( Dicyclohexylphosph F) -1,1'-biphenyl (Cy-BIPHEMP), 2,2'-dimethoxy-6,6'-bis (diphenylphosphino) -1,1'-biphenyl (MeO-BIPHEP), 2,2 ' -Dimethoxy-6,6'-bis (di-p-tolylphosphino) -1,1'-biphenyl (p-Tol-MeO-BIPHEP), 2,2'-dimethoxy-6,6'-bis (di3,5 -Xylylphosphino) -1,1'-biphenyl (DM-MeO-BIPHEP), 2,2'-dimethoxy-6,6'-bis (di-4-methoxy-3,5-dimethylphenylphosphino)- 1,1′-biphenyl (DMM-MeO-BIPHEP), 2,2′-dimethoxy-6,6′-bis (di-4-tert-butoxy-3,5-dimethylphenylphosphino) -1,1′- Biphenyl (DTBM MeO-BIPHEP), 2,2′-dimethoxy-6,6′-bis (dicyclohexylphosphino) -1,1′-biphenyl (Cy-MeO-BIPHEP), 2,2′-dimethyl-3,3′- Dichloro-4,4′-dimethyl-6,6′-bis (di-p-tolylphosphino) -1,1′-biphenyl (p-Tol-CM-BIPHEMP), 2,2′-dimethyl-3,3′- Dichloro-4,4′-dimethyl-6,6′-bis (di3,5-xylylphosphino) -1,1′-biphenyl (DM-CM-BIPHEMP), 2,2′-dimethyl-3, 3′-dichloro-4,4′-dimethyl-6,6′-bis (di4-methoxy-3,5-dimethylphenylphosphino) -1,1′-biphenyl (DMM-CM-BIPHEMP).

  In the present invention, an asymmetric hydrogenation reaction is carried out with the optically active bidentate phosphine ligand described above and an optically active transition metal complex that becomes a transition metal. Examples of the optically active transition metal complex in this asymmetric hydrogenation reaction include: A compound represented by the following general formula (8) is preferable.

Wherein M represents a transition metal; L represents a ligand; W represents a hydrogen atom, a halogen atom, a carboxylate group, an allyl group, a diene or an anion; Y represents a hydrogen atom, a halogen atom, a carboxylate Group, allyl group, diene, anion or a ligand other than L; Z represents an anion or amine; m, n and r represent an integer of 1 to 5; p, q and s represent 0 to 5 Represents an integer, and p + q + s is 1 or more)

  In the general formula (8), transition metals represented by M include iridium (Ir), rhodium (Rh), ruthenium (Ru), palladium (Pd), nickel (Ni), copper (Cu) or platinum (Pt ) And the like.

  Examples of the ligand represented by L include the optically active bidentate ligands described above.

The following are mentioned as a preferable thing of the transition metal complex represented by General formula (8). That is, M in the general formula (8) is a transition metal selected from the group consisting of iridium, rhodium, ruthenium, palladium, nickel, copper and platinum; L is a phosphine compound of the general formula (1); U, m, n, p, q, r, s are when M is iridium or rhodium, (i) W is chlorine, bromine or iodine, and m = n = p = 1, r = 2, q = s = 0, (ii) W is 1,5-cyclooctadiene, norbornadiene, Z is BF ₄ , ClO ₄ , OTf (Tf is a triflate group (SO ₃ CF ₃ )), PF ₆ , SbF ₆ or BPh ₄ (Ph represents a phenyl group), m = n = p = r = s = 1, q = 0, and (iii) Z represents BF ₄ , ClO ₄ , OTf, PF _6, an SbF _6, or BPh _4, indicates m = r = s = 1, n = 2, q = 0 , M is ruthenium, (i) W is chlorine, bromine or iodine, Z is a trialkylamine, and m = p = s = 1, n = r = 2, q = 0, (ii ) W is chlorine, bromine or iodine, Z is a pyridyl group or a ring-substituted pyridyl group, m = n = r = s = 1, p = 2, q = 0, (iii) W is a carboxylate M = n = r = 1, p = 2, q = s = 0, (iv) W is chlorine, bromine or iodine, Z is dimethylformamide or dimethylacetamide, m = n = R = 1, p = 2, q = 0, s represents an integer of 0 to 4, (v) W is chlorine, bromine or iodine, U is chlorine, bromine or iodine, Z is dialkylammonium An ion, m = n = p = 2, q = 3, r = s = 1, and (vi) W is chlorine, bromine or iodine , U is an aromatic compound or olefin which is a neutral ligand, Z is chlorine, bromine, iodine, I ₃ , BF ₄ , ClO ₄ , OTf, PF ₆ , SbF ₆ or BPh ₄ , m = n = p = q = r = s = 1, (vii) Z is BF ₄ , ClO ₄ , OTf, PF ₆ , SbF ₆ or BPh ₄ , m = n = r = 1, p = q = 0, s = 2, (viii) W and U may be the same or different, and are a hydrogen atom, chlorine, bromine, iodine, carboxyl group or other anionic group, Z is a diamine compound M = n = p = q = r = s = 1, (ix) W is a hydrogen atom, U is chlorine, bromine or iodine, m = p = q = r = 1, n = 2, s = 0, (x) W is a hydrogen atom, Z is BF ₄ , ClO ₄ , OTf, PF ₆ , SbF ₆ or BPh ₄ , m = n = p = r = s = 1, q = 0, (xi) W is chlorine, bromine or iodine, U is a monovalent phosphine ligand, Z is chlorine, bromine or iodine, m = n = p = q = 1, r = z = 2, (xii) W and U are the same or different and are chlorine, bromine or iodine, m = n = p = q = r = 1, when s = 0 and M is palladium, (i) W is chlorine, bromine or iodine, m = n = r = 1, p = 2, q = s = 0, and (ii) W is An allyl group, m = n = p = r = 1, q = s = 0, and (iii) Z is BF ₄ , ClO ₄ , OTf, PF ₆ , SbF ₆ or BPh ₄ , m = n = R = 1, p = q = 0, s = 2, and (iv) W is an alkyl nitrile having 1 to 5 carbon atoms, benzonitrile, phthalonitrile, pyridine, dimethyl sulfoxide, dimethylform Amide, a dimethylacetamide or acetone, Z is _{BF 4, ClO 4, OTf,} PF 6, a SbF ₆ or BPh _4, shows the m = n = r = 1, p = s = 2, q = 0, When M is nickel, (i) W is chlorine, bromine or iodine, and m = n = r = 1, p = 2, q = s = 0, and (ii) Z is BF ₄ , ClO ₄ , OTf, PF ₆ , SbF ₆ or BPh ₄ , m = n = r = 1, p = q = 0, s = 2, and when M is copper, W is a hydrogen atom, fluorine, chlorine, bromine or Iodine, m = p = 4, n = 2, r = 1, q = s = 0, and when M is platinum, (i) W is an alkyl nitrile, benzonitrile, phthalo having 1 to 5 carbon atoms Nitrile, pyridine, dimethyl sulfoxide, dimethylformamide, dimethylacetamide or acetone, Z is BF ₄ , C lO ₄ , OTf, PF ₆ , SbF ₆ or BPh ₄ , m = n = r = 1, p = s = 2, q = 0, (ii) W is chlorine, bromine or iodine, m = N = r = 1, p = 2, q = s = 0, (iii) W is chlorine, bromine or iodine, U is SnCl ₂ , m = n = q = r = 1, p = 2 and s = 0, (iv) W is chlorine, bromine or iodine, U is SnCl ₃ , m = n = p = q = r = 1, s = 0 Compounds.

  Although it does not restrict | limit especially as a manufacturing method of the complex (8) of a transition metal phosphine complex, For example, it can manufacture using the method shown next, or the method according to this. In the following transition metal phosphine complex formula, cod is 1,5-cyclooctadiene, nbd is norbornadiene, Ph is a phenyl group, Ac is an acetyl group, acac is acetylacetonate, and dmf is Dimethylformamide, en represents ethylenediamine, DPEN represents 1,2-diphenylethylenediamine, and DAIPEN represents 1,1-di (p-methoxyphenyl) -2-isopropylethylenediamine.

Rhodium complex: As a specific example for producing a rhodium complex, for example, described in the Chemical Society of Japan, “Fourth Edition, Experimental Chemistry Course”, Volume 18, Organometallic Complex, 1991, pp. 339-344 (Maruzen) According to the above method, bis (1,5-cyclooctadiene) rhodium (I) tetrafluoroborate ([Rh (cod) ₂ ] BF ₄ ) is reacted with the compound (1) of the present invention for synthesis. Can do.

Specific examples of the rhodium complex include the following.
[Rh (L) Cl] ₂ , [Rh (L) Br] ₂ , [Rh (L) I] ₂ ,
[Rh (cod) (L)] OTf, [Rh (cod) (L)] BF ₄ ,
[Rh (cod) (L)] ClO ₄ , [Rh (cod) (L)] SbF ₆ ,
[Rh (cod) (L)] PF ₆ , [Rh (cod) (L)] BPh ₄ ,
[Rh (nbd) (L)] OTf, [Rh (nbd) (L)] BF ₄ ,
[Rh (nbd) (L)] ClO ₄ , [Rh (nbd) (L)] SbF ₆ ,
[Rh (nbd) (L)] PF ₆ , [Rh (nbd) (L)] BPh ₄ ,
[Rh (L) ₂ ] OTf, [Rh (L) ₂ ] BF ₄ , [Rh (L) ₂ ] ClO ₄ ,
[Rh (L) ₂ ] SbF ₆ , [Rh (L) ₂ ] PF ₆ , [Rh (L) ₂ ] BPh ₄ .

Ruthenium complex: As a method for producing a ruthenium complex, for example, according to the literature (J. Chem. Soc., Chem. Commun., 922, 1985), [(1,5-cyclooctadiene) Dichlororuthenium] ([Ru (cod) Cl ₂ ] _n ) and the compound of general formula (7) can be prepared by heating to reflux in an organic solvent in the presence of a trialkylamine. In addition, in accordance with the method described in JP-A-11-269185, bis [dichloro (benzene) ruthenium] ([Ru (benzene) Cl ₂ ] ₂ ) and the compound of the general formula (7) are added in the presence of a dialkylamine. It can be prepared by heating to reflux in an organic solvent. Further, in accordance with the method described in the literature (J. Chem. Soc., Chem. Commun., 1208, 1989), bis [diiodo (para-cymene) ruthenium] ([Ru (p-cymene) I _{2 2} ) and the compound of the general formula (7) can be prepared by heating and stirring in an organic solvent. Furthermore, Ru ₂ Cl ₄ (L) ₂ obtained according to the method of the literature (J. Chem. Soc., Chem. Commun., Page 992, 1985) according to the method described in JP-A-11-189600. It can be synthesized by reacting NEt ₃ and a diamine compound in an organic solvent.

Specific examples of the ruthenium complex include the following.
Ru (OAc) ₂ (L), Ru (OCOCF ₃ ) ₂ (L), Ru ₂ Cl ₄ (L) ₂ NEt ₃ ,
RuHCl (L), RuHBr (L), RuHI (L),
[{RuCl (L)} ₂ (μ-Cl) ₃ ] [Me ₂ NH ₂ ],
[{RuBr (L)} ₂ (μ-Br) ₃ ] [Me ₂ NH ₂ ],
[{RuI (L)} ₂ (μ-I) ₃ ] [Me ₂ NH ₂ ],
[{RuCl (L)} ₂ (μ-Cl) ₃ ] [Et ₂ NH ₂ ],
[{RuBr (L)} ₂ (μ-Br) ₃ ] [Et ₂ NH ₂ ],
[{RuBr (L)} ₂ (μ-I) ₃ ] [Et ₂ NH ₂ ],
[RuCl [PPh ₃ ] (L)] ₂ (μ-Cl) ₂ , [RuBr [PPh ₃ ] (L)] ₂ (μ-Br) ₂ ,
[RuI [PPh ₃ ] (L)] ₂ (μ-I) ₂ , RuCl ₂ (L), RuBr ₂ (L), RuI ₂ (L), [RuCl ₂ (L)] (dmf) _n , RuCl ₂ (L) (pyridine) ₂ ,
RuBr ₂ (L) (pyridine) ₂ , RuI ₂ (L) (pyridine) ₂ ,
RuCl ₂ (L) (2,2′-dipyridine),
RuBr ₂ (L) (2,2′-dipyridine),
RuI ₂ (L) (2,2′-dipyridine),
[RuCl (benzone) (L)] Cl,
[RuBr (benzone) (L)] Br, [RuI (benzone) (L)] I,
[RuCl (p-cymene) (L)] Cl 2,
[RuBr (p-cymene) (L)] Br,
[RuI (p-cymene) ( L)] I, [RuI (p-cymene) (L)] I 3,
[Ru (L)] (OTf) ₂ , [Ru (L)] (BF ₄ ) ₂ , [Ru (L)] (ClO ₄ ) ₂ ,
[Ru (L)] (SbF ₆ ) ₂ , [Ru (L)] (PF ₆ ) ₂ , [Ru (L)] (BPh ₄ ) ₂ , [RuCl ₂ (L)] (en), [RuBr ₂ (L)] (en), [RuI ₂ (L)] (en),
[RuH ₂ (L)] (en), [RuCl ₂ (L)] (DPEN),
[RuBr ₂ (L)] (DPEN), [RuI ₂ (L)] (DPEN),
[RuH ₂ (L)] (DPEN), [RuCl ₂ (L)] (DAIPEN),
[RuBr ₂ (L)] (DAIPEN), [RuI ₂ (L)] (DAIPEN),
[RuH ₂ (L)] (DAIPEN).

Iridium Complex: As a method for producing an iridium complex, for example, according to the method described in the literature (J. Organomet. Chem., 1992, 428, 213), the compound of the general formula (7) and [(1 , 5-cyclooctadiene) (acetonitrile) iridium] tetrahydroborate ([Ir (cod) (CH ₃ CN) ₂ ] BF ₄ ) can be prepared by reacting with stirring in an organic solvent.

Specific examples of the iridium complex include the following.
[Ir (L) Cl] ₂ , [Ir (L) Br] ₂ , [Ir (L) I] ₂ ,
[Ir (cod) (L)] OTf, [Ir (cod) (L)] BF ₄ ,
[Ir (cod) (L)] ClO ₄ , [Ir (cod) (L)] SbF ₆ ,
[Ir (cod) (L)] PF ₆ , [Ir (cod) (L)] BPh ₄ ,
[Ir (nbd) (L)] OTf, [Ir (nbd) (L)] BF ₄ ,
[Ir (nbd) (L)] ClO ₄ , [Ir (nbd) (L)] SbF ₆ ,
[Ir (nbd) (L)] PF ₆ , [Ir (nbd) (L)] BPh ₄ ,
[Ir (L) ₂ ] OTf, [Ir (L) ₂ ] BF ₄ , [Ir (L) ₂ ] ClO ₄ ,
[Ir (L) ₂ ] SbF ₆ , [Ir (L) ₂ ] PF ₆ , [Ir (L) ₂ ] BPh ₄ ,
IrCl (cod) (CO) (L), IrBr (cod) (CO) (L),
IrI (cod) (CO) (L).

Palladium complex: As a method for producing a palladium complex, for example, literature (J. Am. Chem. Soc., 1991, 113, 9887; J. Chem. Soc., Dalton Trans., 2246-2249, 1980; Tetrahedron Letters, 37, 6351-6354, 1996), a compound of general formula (7) and π-allyl palladium chloride ([(π-allyl) PdCl] ₂ ) It can be prepared by reacting.

Specific examples of the palladium complex include the following.
PdCl ₂ (L), PdBr ₂ (L), PdI ₂ (L), Pd (OAc) ₂ (L),
Pd (OCOCF ₃ ) ₂ (L), [(π-allyl) Pd (L)] Cl,
[(Π-allyl) Pd (L)] Br, [(π-allyl) Pd (L)] I,
[(Π-allyl) Pd (L)] OTf, [(π-allyl) Pd (L)] BF ₄ ,
[(Π-allyl) Pd (L)] ClO ₄ , [(π-allyl) Pd (L)] SbF ₆ , [(π-allyl) Pd (L)] PF ₆ , [(π-allyl) Pd ( L)] BPh ₄ ,
[(Pd (L))] (OTf) ₂ , [(Pd (L))] (BF ₄ ) ₂ ,
[(Pd (L))] (ClO ₄ ) ₂ , [(Pd (L))] (SbF ₆ ) ₂ ,
[(Pd (L))] (PF ₆ ) ₂ , [(Pd (L))] (BPh ₄ ) ₂ ,
PhCH ₂ Pd (L) Cl, PhCH ₂ Pd (L) Br,
PhCH ₂ Pd (L) I, PhPdCl (L), PhPdBr (L), PhPdI (L), Pd (L), [Pd (L) (PhCN) ₂ ] [BF ₄ ] ₂ .

Nickel complex: As a method for producing a nickel complex, for example, the method of the Chemical Society of Japan, “Fourth Edition, Experimental Chemistry Course”, Vol. 18, Organometallic Complex, 1991, page 376 (Maruzen), literature (J Am. Chem. Soc., 1991, 113, 9887), the compound of general formula (7) and nickel chloride (NiCl ₂ ) are dissolved in an organic solvent and heated and stirred. Can be prepared.

Specific examples of the nickel complex include the following.
NiCl ₂ (L), NiBr ₂ (L), NiI ₂ (L).

Copper complex: As a method for producing a copper complex, for example, according to the method of the Chemical Society of Japan “4th edition Experimental Chemistry Course” Vol. 18, Organometallic Complex, 1991, pp. 444-445 (Maruzen), It can be prepared by dissolving the compound of the general formula (7) and copper (I) chloride (CuCl ₂ ) in an organic solvent and heating and stirring.

Specific examples of the copper complex include the following.
Cu ₄ F ₄ (L) ₂ , Cu ₄ Cl ₄ (L) ₂ , Cu ₄ Br ₄ (L) ₂ , Cu ₄ I ₄ (L) ₂ ,
Cu ₄ H ₄ (L) ₂ .

Platinum complex: As a method for producing a platinum complex, for example, a compound of the general formula (7) and dibenzonitrile dichloroplatinum (RtCl) are prepared according to the method described in the literature (Orgomometallics, 1991, Vol. 10, page 2046). ₂ (PhCN) ₂ ) can be prepared by dissolving in an organic solvent and stirring under heating, and a Lewis acid (SnCl ₂ or the like) may be added if necessary.

Specific examples of the platinum complex include the following.
PtCl ₂ (L), PtBr ₂ (L), PtI ₂ (L), PtCl ₂ (L) (SnCl ₂ ), PtCl (L) (SnCl ₃ ).

  A more preferable catalyst in the asymmetric hydrogenation reaction of the present invention is a complex composed of an optically active bidentate phosphine ligand and a transition metal, which are one kind selected from rhodium, iridium and ruthenium as a transition metal complex. Most preferably, it is a complex obtained by adding an ammonium salt, a phosphonium salt or an alkali metal salt to a complex composed of such an optically active phosphine and a transition metal, followed by hydrogenation.

  A system in which selectivity is increased in the presence of a complex obtained by adding an ammonium salt, a phosphonium salt or an alkali metal salt to a complex composed of such an optically active phosphine and a transition metal complex and hydrogenating the complex is examined. I liked the following system.

  Formula (9),

(Wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ each independently represents an alkyl group having 1 to 16 carbon atoms, a phenyl group or a benzyl group, B represents a nitrogen atom or a phosphorus atom, and G represents fluorine. , A quaternary ammonium salt or a quaternary phosphonium salt represented by, for example, Me ₄ NCl, Me ₄ NBr, Me ₄ NI, Et ₄ NCl, Et ₄ NBr, Et ₄ NI, Bu ₄ NCl, Bu ₄ NBr, Bu ₄ NI,
(Benzyl) Me ₃ NCl, (Benzyl) Me ₃ NBr,
(Benzyl) Me ₃ NI, (Benzyl) Et ₃ NCl,
(Benzyl) Et ₃ NBr, (Benzyl) Et ₃ NI, (C ₈ H ₁₇ ) Me ₃ NCl,
(C ₈ H ₁₇ ) Me ₃ NBr, (C ₈ H ₁₇ ) Me ₃ NI, (C ₁₆ H ₃₃ ) Me ₃ NCl,
(C ₁₆ H ₃₃ ) Me ₃ NBr, (C ₁₆ H ₃₃ ) Me ₃ NI, Me ₄ NOTf, Me ₄ NOTs,
Me ₄ NOAc, Me ₄ NOCOCF ₃ , n-Bu ₄ NOTf, n-Bu ₄ NOTs,
Quaternary ammonium salts such as n-Bu ₄ NOAc, n-Bu ₄ NOCOCF ₃ , MePh ₃ PCl, MePh ₃ PBr, MePh ₃ PI, EtPh ₃ PCl, EtPh ₃ PBr, EtPh ₃ PI,
BuPh ₃ PCl, BuPh ₃ PBr, BuPh ₃ PI, Ph ₄ PCl, Ph ₄ PBr,
Ph ₄ PI, (C ₆ H ₁₃ ) Ph ₃ PCl, (C ₆ H ₁₃ ) Ph ₃ PBr, (C ₆ H ₁₃ ) Ph ₃ PI,
(C ₇ H ₁₅ ) Ph ₃ PCl, (C ₇ H ₁₅ ) Ph ₃ PBr, (C ₇ H ₁₅ ) Ph ₃ PI,
(C ₈ H ₁₇ ) Ph ₃ PCl, (C ₈ H ₁₇ ) Ph ₃ PBr, (C ₈ H ₁₇ ) Ph ₃ PI,
(C ₁₆ H ₃₃ ) Ph ₃ PCl, (C ₁₆ H ₃₃ ) Ph ₃ PBr, (C ₁₆ H ₃₃ ) Ph ₃ PI,
(C ₁₆ H ₃₃ ) Bu ₃ PCl, (C ₁₆ H ₃₃ ) Bu ₃ PBr, (C ₁₆ H ₃₃ ) Bu ₃ PI,
ClPPh ₃ CH ₂ PPh ₃ Cl, ClPPh ₃ (CH ₂ ) ₂ PPh ₃ Cl,
ClPPh ₃ (CH ₂ ) ₃ PPh ₃ Cl, ClPPh ₃ (CH ₂ ) ₄ PPh ₃ Cl,
ClPPh ₃ (CH ₂ ) ₅ PPh ₃ Cl, ClPPh ₃ (CH ₂ ) ₆ PPh ₃ Cl,
BrPPh ₃ CH ₂ PPh ₃ Br, BrPPh ₃ (CH ₂ ) ₂ PPh ₃ CBr,
BrPPh ₃ (CH ₂ ) ₃ PPh ₃ Br, BrPPh ₃ (CH ₂ ) ₄ PPh ₃ Br,
BrPPh ₃ (CH ₂ ) ₅ PPh ₃ Br, BrPPh ₃ (CH ₂ ) ₆ PPh ₃ Br,
IPPh ₃ CH ₂ PPh ₃ I, IPPh ₃ (CH ₂ ) ₂ PPh ₃ I,
IPPh ₃ (CH ₂ ) ₃ PPh ₃ I, IPPh ₃ (CH ₂ ) ₄ PPh ₃ I,
A system using a quaternary phosphonium salt such as IPPh ₃ (CH ₂ ) ₅ PPh ₃ I or IPPh ₃ (CH ₂ ) ₆ PPh ₃ I is preferred.

  Moreover, general formula (10),

(Wherein M ′ represents a metal of Li, Na or K, and Z ′ represents a halogen atom of Cl, Br or I)
Specifically, for example, those using metal salts such as LiCl, LiBr, LiI, NaCl, NaBr, NaI, KCl, KBr, and KI are preferable. Furthermore, ammonium salts such as (Bn) Et ₃ NCl, (Bn) Et ₃ NBr, (Bn) Et ₃ NI can be selected, and BuPh ₃ PCl, BuPh ₃ PBr, BuPh ₃ PI, (C ₆ H ₁₃ ) Ph. Phosphonium salts such as ₃ PBr, BrPPH ₃ (CH ₂ ) ₄ PPh ₃ Br can be selected to obtain high selectivity (Bn: benzyl group, Et: ethyl group, Ph: phenyl group, Bu: butyl group) .

Further, the optically active bidentate phosphine ligand, is in the BINAP compounds can be selected DM-BINAP, can select DM-H ₈ -BINAP is in H ₈ -BINAP such, further SEGPHOS DTBM-SEGPHOS can be selected from the class, and high selectivity can be obtained.

  Since these optically active bidentate phosphine ligands exist in both (S) -form and (R) -form, either one is selected depending on the absolute configuration of the target optically active alkylphthalide (1). Should be selected. That is, when the (Z) -isomer is used as the substrate, for example, when DTBM-SEGPHOS is used as the ligand, the (-)-isomer is used to obtain the (S) -isomer, and the (R) -isomer is obtained. The (+)-form may be used to obtain On the other hand, when the (E) -isomer is used as the substrate, the (+)-isomer is used to obtain the (S) -isomer, and the (-)-isomer is used to obtain the (R) -isomer.

  In addition, it is preferable that the usage-amount of a transition metal-optically active phosphine complex is about 5000-150,000 mol with respect to alkylidene phthalides (2). The amount of the additive (ammonium salt, phosphonium salt or alkali metal salt) used is preferably about 0.2 to 2.0 equivalents relative to the transition metal-optically active bidentate phosphine complex.

Any suitable reaction solvent can be used as long as it can solubilize the asymmetric hydrogenation raw material and the catalyst system. For example, aromatic hydrocarbon solvents such as toluene and xylene, aliphatic hydrocarbon solvents such as pentane and hexane; halogen-containing hydrocarbon solvents such as methylene chloride; ether solvents such as ether and tetrahydrofuran; methanol, ethanol, 2- Alcohol solvents such as propanol, butanol and benzyl alcohol; organic solvents containing heteroatoms such as acetonitrile, DMF and DMSO can be used. Preferably, an alcohol solvent and a mixed solvent with an alcohol solvent are used. The amount of solvent is determined by the solubility and economics of the reaction substrate. For example, although it can be carried out in a state close to solvent-free from a low concentration of 1% or less depending on the substrate, it is preferably used in a volume of 0.1 to 2.0. The pressure of hydrogen in the present invention, 1 to 100 kg / cm ² in consideration of economic efficiency (0.1 to 10 MPa), preferably in the range of more 5~50Kg / cm ² (0.5~5MPa). About reaction temperature, although it can carry out at 0-150 degreeC, the range of 10-50 degreeC is more preferable. Moreover, although reaction time changes with reaction conditions, such as reaction substrate density | concentration, temperature, and pressure, reaction is completed in several minutes-30 hours. After completion of the reaction, the desired product can be isolated by carrying out ordinary post-treatment.

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. In addition, the apparatus used for the measurement of the physical property in each Example is as follows.

Gas chromatography Equipment used: HP-6890 (manufactured by Hewlett Packard)
Column: Neutrabond-1 (30 m × 0.25 μm)
Inj. temp. : 250 ° C
Det. temp. : 250 ° C
Initial temp. : 100 ° C
Optical rotation: Equipment used: DIP-360 (manufactured by JASCO Corporation)

Example 1 Synthesis of (Z) -octylidenephthalide 3.3 g (0.136 mol) of magnesium was weighed into a 300 mL four-necked flask, purged with nitrogen, added with 10 mL of THF, and heated at 75 ° C. for about 5 to 10 minutes. Then, 0.2 g of octyl bromide was added dropwise to confirm the start of the reaction. After stirring for 10 minutes, 23.8 g (0.16 mol) of octyl chloride diluted with 50 mL of THF was added dropwise over 1.5 hours. The temperature reached 69-71 ° C. due to exotherm, and the solvent was refluxed. After completion of the dropwise addition, 105 mL of THF was added, and stirring was further continued for 1 hour at an internal temperature of 70 ° C. to prepare an octylmagnesium chloride solution (Grignia reagent).

To a 500 mL four-necked flask, 25.0 g (0.123 mol) of phthaloyl dichloride was charged, and after replacing with nitrogen, 50 mL of THF was added. The mixture was cooled to −30 ° C. in a dry ice / acetone bath, and the Grignard reagent obtained by the above reaction was added dropwise over 1.5 hours with vigorous stirring. After completion of the dropwise addition, the temperature was further maintained at −30 ° C. for 30 minutes. Thereafter, the cooling bath was removed, and the stirring was stopped when the temperature in the tank reached 0 ° C. to complete the reaction. THF was collected under reduced pressure, toluene and water and 100 mL of each were added thereto, and 6 mL of 10% hydrochloric acid was added dropwise and stirred for about 5 minutes, followed by liquid separation to remove the magnesium salt. Subsequently, the plate was washed with 200 mL of 5% caustic soda, separated, and further washed twice with 100 mL of 10% saline.
After toluene recovery, column chromatography was performed to obtain (Z) -octylidenephthalide in a yield of 61.0%.

Example 2 Synthesis of (R) -octylphthalide In a 200 mL autoclave, 3.8 mg of [Rh (cod) ₂ ] PF ₆ , 9.7 mg of (+)-DTBM-SEGPHOS, Br ⁻ Ph ₃ P ⁺ (CH ₂ ) ₄ P ⁺ Ph ₃ Br ⁻ (DTPPBB) 7.6 mg and (Z) -octylidenephthalide 10.0 g obtained in Example 1 were charged, hydrogen was charged to 4.0 Mpa at room temperature, and the mixture was stirred at 70 ° C. for 19 hours. did. After completion of the reaction, distillation was carried out to obtain 9.5 g (purity 98.2%) of colorless and transparent octylphthalide. 9.5 g of the obtained octylphthalide was dissolved in 60 mL of aqueous methanol (S / S = 6) and then cooled to 7.0 g of (R) -octylphthalide (purity 100%, [α] ²⁵ _D :- 55.4 ° (c = 1.09, n-hexane) was obtained as white crystals.

Examples 3-4
The rhodium catalyst, the substrate / catalyst molar ratio (S / C), the solvent capacity / substrate mass ratio (S / S), the reaction temperature and the reaction conditions were changed as shown in Table 1, and the reaction was carried out in the same manner as in Example 2. The results are shown in Table 1.

Claims (6)

The following general formula (3):
(In the formula, ring A represents an optionally substituted benzene ring ; X and X ′ each independently represents a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen-substituted alkylsulfonyloxy group. )
A phthalic acid derivative represented by the following general formula (4):
(Wherein Y represents a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group or a halogen-substituted alkylsulfonyloxy group; l represents an integer of 2 to 8)
Is reacted with a magnesium compound represented by the following general formula (2):
(Wherein, rings A and l are as defined above; the wavy line indicates a double bond cis-form and / or trans-form)
General formula (1) characterized in that an alkylidenephthalide represented by the following formula is obtained and then asymmetrically hydrogenated:
(In the formula, rings A and l are as defined above; * indicates an asymmetric carbon atom)
The manufacturing method of optically active alkylphthalides represented by these. The following general formula (3):
(In the formula, ring A represents an optionally substituted benzene ring ; X and X ′ each independently represents a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen-substituted alkylsulfonyloxy group. )
A phthalic acid derivative represented by the following general formula (4):
(Wherein Y represents a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group or a halogen-substituted alkylsulfonyloxy group; l represents an integer of 2 to 8)
The following general formula (2) characterized by reacting with a magnesium compound represented by the formula:
(Wherein, rings A and l are as defined above; the wavy line indicates a double bond cis-form and / or trans-form)
The manufacturing method of the alkylidene phthalides represented by these. The process according to claim 1, wherein the performing asymmetric hydrogenation with complexes comprising an optically active phosphine compound of a transition metal. The optically active phosphine compound has the following general formula (7) :
(In the formula, R ^{1 to} R ⁴ each independently represents an aromatic group which may have a substituent or a cycloalkyl group having 3 to 10 carbon atoms, or R ¹ and R ² , R ³ and R ⁴ may each form a heterocyclic ring together with adjacent phosphorus atoms; R ⁵ and R ⁶ each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms. alkoxy group, diamino group (containing 1-5 alkyl carbon atoms), shows a 5-8 membered cyclic amino group or a halogen atom; R ⁷ is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, A di (C 1-5 alkyl) amino group, a 5- to 8-membered cyclic amino group, or a halogen atom; and R ⁵ and R ⁶ , R ⁶ and R ⁷ are combined together to form a condensed benzene ring , Condensed substituted benzene ring, trimethylene group, tetramethylene group, pentamethylene group, methylenedi Alkoxy group, may form an ethylenedioxy group or a trimethylenedioxy group)
The production method according to claim 3 , which is an optically active phosphine compound represented by the formula: The method according to claim 3 or 4 , wherein an asymmetric hydrogenation reaction is carried out with an optically active phosphine complex comprising an optically active phosphine compound and a transition metal complex selected from rhodium, iridium and ruthenium. Asymmetric hydrogenation reaction is performed by adding an ammonium salt, a phosphonium salt or an alkali metal salt to an optically active phosphine complex comprising an optically active phosphine compound and a transition metal complex selected from rhodium, iridium and ruthenium. The manufacturing method of any one of Claims 3-5 to do.