JPH09235255A - Production of benzhydrol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an optically active benzhydrol derivative in a high yield and at a high purity, useful as a synthetic intermediate for a medicine, a liquid crystal material, etc., by a simple operation. SOLUTION: This benzhydrol derivative of formula II (* shows the position of an asymmetric carbon) is obtained by performing the hydrogenation reaction of a benzophenone derivative of formula I (R is a substitutable amino; A ring, B ring are each further substitutable) or salt thereof in the presence of an asymmetric hydrogenation catalyst, in a solvent (e.g. 2-propanol), under 1-100 atm hydrogen pressure at 20-90 deg.C for 2-48hr. As the asymmetric hydrogenation catalyst, a material consisting of a transition metal complex (e.g.; ruthenium complex), a base (e.g.; poatssium hydroxide) and an optically active nitrogen compound (e.g.; 1,2-diphenylethylenediamine) is used. The transition metal complex is used by (1/100)-(1/100000) molar ratio based on the compound of formula I, and 0.001-0.5mol equivalent base and 1-20mol equivalent optically active nitrogen compound based on the transition metal complex, are used.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a benzhydrol derivative, and more specifically, the practicality of an optically active benzhydrol derivative useful in various applications such as synthetic intermediates for pharmaceuticals and liquid crystal materials. The present invention relates to a novel manufacturing method excellent in

[0002]

2. Description of the Related Art Conventionally, as methods for synthesizing optically active alcohols, 1) a method using an enzyme such as baker's yeast and 2) a method for asymmetric hydrogenating a carbonyl compound using a metal complex have been known. Has been. In particular, as the latter asymmetric hydrogenation method, many methods have been proposed as follows. For example, (1) "Asymmetric Catalysis In Or
ganic Synthesis, pp. 56-82 (1994) Ed. R. No.
a method for asymmetric hydrogenation of a carbonyl compound having a functional group with an optically active ruthenium catalyst described in detail in "yori", (2) "Chem. Rev., Vol. 92, 1051-10.
69 (1992) ”, a hydrogen transfer reduction reaction with an asymmetric complex catalyst of ruthenium, rhodium and iridium, (3)“ Oil Chemistry, pages 828-831 (198).
0) ”and“ Advances in Catalysis, Vol. 32, 21
5 (1983) Ed. Y. Izumi ", a method for asymmetric hydrogenation using a tartaric acid-modified nickel catalyst, (4)" Asymmetric Synthesis, Vol. 5, Chap. 4 "
(1985) Ed. JD Morrison "and" J. Organome
t. Chem., Vol. 346, pp. 413-424 (198).
8) ”, the method by asymmetric hydrosilylation, (5)“ J. Chem. Soc., Perkin Trans. I, 203.
9-2044 (1985) "and" J. Am. Chem. So
c., Vol. 109, pp. 5551-5553 (1987) "
Borane reduction in the presence of an asymmetric ligand described in (6) “J. Am. Chem. Soc., Vol. 117, 26”.
A method for asymmetric hydrogenating acetophenones with an asymmetric complex catalyst of potassium hydroxide, an optically active diamine, and ruthenium described in "75-2676 (1995)" is known.

However, among the above-mentioned methods for synthesizing optically active alcohols, the synthesizing method using an enzyme is complicated in operation, there are restrictions on the kinds of reaction substrates, and the absolute configuration of the obtained alcohols is also specific. It has the drawback of being limited. In addition, in the case of a synthetic method using a transition metal asymmetric hydrogenation catalyst, there is a problem in terms of reaction rate, and unexpectedly, it is not effective for relatively simple carbonyl compounds. We must consider gender.

Although various transition metal catalysts for asymmetric hydrogenation of carbonyl compounds have been reported, these catalysts generally have acetophenone derivative as the reaction substrate in the asymmetric hydrogenation reaction of carbonyl compounds. It is relatively good for ketones having an aromatic ring group and an aliphatic group, but hydrogenation is less likely to occur when the reaction substrate is a ketone having two aromatic ring groups. It is known.

On the other hand, a method of hydrogenating a benzophenone derivative using a transition metal catalyst can be considered as a method for producing a benzhydrol derivative useful in various applications such as synthetic intermediates for pharmaceuticals and liquid crystal materials. It was not possible to obtain good results corresponding to cases such as.

In particular, as in the field of medicine, when only a specific absolute configuration is useful as a medicine,
Even if the hydrogenation was successful, the obtained product could only be used if it was an optically active substance, and the application of the above method could not be expected for these specific ketones.

[0007]

Therefore, an object of the present invention is to asymmetrically hydrogenate a benzophenone derivative or a salt thereof by a simple operation to obtain a benzhydrol derivative having a desired absolute configuration in high yield and high optical purity. It is to provide a novel manufacturing method that can be obtained.

[0008]

Under such circumstances, as a result of intensive studies by the present inventors, as a result, a benzophenone derivative or a salt thereof is asymmetrically hydrogenated in the presence of a specific asymmetric hydrogenation catalyst. As a result, they have found that the above object can be achieved and completed the present invention.

That is, the present invention provides the following general formula (1):

[0010]

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A benzophenone derivative represented by the formula (wherein R represents an amino group which may have a substituent and each of A ring and B ring may further have a substituent) or a salt thereof. The following general formula (2) characterized by hydrogenation in the presence of an asymmetric carbonization catalyst

[0012]

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## STR1 ## wherein R, A ring and B ring have the same meanings as described above, and * indicates the position of the asymmetric carbon, and a method for producing an optically active benzhydrol derivative or a salt thereof. Is provided.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the above-mentioned benzophenone derivative (1) which is a reaction substrate, R is an amino group which may have 1 or 2 substituents, and preferred specific examples include an unsubstituted amino group or a lower group. Examples thereof include an amino group in which an alkyl group, an acyl group or a protecting group is mono-substituted. The amino group mono-substituted by a lower alkyl group is an amino group mono-substituted by an alkyl group having 1 to 6 carbon atoms, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, n-butylamino group, Examples thereof include an isobutylamino group, a tert-butylamino group, an n-pentylamino group, a 2,2-dimethylpropylamino group (neopentylamino group) and the like, and particularly a 2,2-dimethylpropylamino group (neopentylamino group). Is preferred.

Examples of the monoacylamino group include formylamino group, acetylamino group, propionylamino group, butyrylamino group, valerylamino group, isovalerylamino group, pivaloylamino group, palmitoylamino group, stearoylamino group and oleoylamino group. And a monoalkanoylamino group having 1 to 18 carbon atoms, of which a pivaloylamino group is particularly preferable.

The protecting group is a group which can be easily eliminated, and examples thereof include an optionally substituted benzyloxycarbonyl group and an alkoxycarbonyl group. As the alkoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,
Examples thereof include alkoxycarbonyl groups having 1 to 4 carbon atoms such as an isopropyloxycarbonyl group, a butoxycarbonyl group, an isobutyloxycarbonyl group, and a tert-butyloxycarbonyl group. Of these, a tert-butyloxycarbonyl group is particularly preferable. The phenyl group of the benzyloxycarbonyl group may be substituted with a nitro group, a methoxy group or the like, and specific examples thereof include a p-nitrobenzyloxycarbonyl group.

Rings A and B each may further have a substituent, and specific examples of the substituent include a halogen atom, a hydroxy group, and an optionally halogenated alkyl group having 1 to 4 carbon atoms. And an optionally halogenated alkoxy group having 1 to 4 carbon atoms, an alkanoyl group having 1 to 5 carbon atoms, and an amino group optionally substituted by an alkyl group having 1 to 4 carbon atoms. Fluorine as the halogen atom,
Examples thereof include chlorine, bromine and iodine, chlorine and bromine are preferable, and chlorine is particularly preferable. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group and a tert-butyl group, and a methyl group is particularly preferable. Further, these alkyl groups may be substituted with a halogen atom.

Examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, an n-butyloxy group, an isobutyloxy group and a tert-butyloxy group, and a methoxy group is particularly preferable. preferable. Further, these alkoxy groups may be substituted with a halogen atom. Examples of the alkanoyl group having 1 to 5 carbon atoms include formyl group, acetyl group, ethylcarbonyl group, propylcarbonyl group, isopropylcarbonyl group, butylcarbonyl group, isobutylcarbonyl group and pivaloyl group, and particularly acetyl group and pivaloyl group. preferable.

Examples of the amino group substituted with an alkyl group having 1 to 4 carbon atoms include a monoalkylamino group substituted with one alkyl group and a dialkylamino group substituted with two alkyl groups. Examples of the monoalkylamino group include amino groups substituted with an alkyl group having 1 to 4 carbon atoms in the monoalkylamino group. Further, as the dialkylamino group, a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, a di-n-butylamino group, a diisobutylamino group, a ditertiary amino group.
Examples thereof include a t-butylamino group, and among these, a dimethylamino group is particularly preferable.

In the benzophenone derivative (1), A
The ring is preferably substituted with an optionally halogenated alkoxy group having 1 to 4 carbon atoms, and is particularly substituted with two optionally halogenated alkoxy group having 1 to 4 carbon atoms (particularly a methoxy group). The above are more preferable, and those substituted at the ortho and para positions are more preferable. Moreover, as the B ring, those having 1 or 2 halogen atoms as substituents are preferable, and those having the para-position of the group -R substituted are particularly preferable. It is preferable that the A ring and the B ring are not in a symmetric relationship in which substituents of the same kind are substituted at the same position.

The benzophenone derivative (1), which is the starting compound in the present invention, has a benzophenone skeleton of 2
Although the group -R is substituted at the -position, the group -R is substituted at this position, whereby a benzhydrol derivative having a high optical purity (% ee) can be obtained. This means
It is also clear from the asymmetric hydrogenation of the compound in which the amino group is substituted at the 4-position of the benzophenone skeleton in Comparative Example 1 described later, the optical purity is as low as 20.44% ee.

Examples of the benzophenone derivative (1) as the starting compound in the present invention include those shown in the following Tables 1 to 7, but are not limited to these. In the following, Me is a methyl group, Et is an ethyl group,
iPr is an isopropyl group, iBu is an isobutyl group, dm
Pr means a 2,2-dimethylpropyl group, Ac means an acetyl group, Piv means a pivaloyl group, and Bz means a benzyl group.

[0023]

[Table 1]

[0024]

[Table 2]

[0025]

[Table 3]

[0026]

[Table 4]

[0027]

[Table 5]

[0028]

[Table 6]

[0029]

[Table 7]

In the present invention, of these, compounds 2, 3, 38, 39, 65, 66, 86 and 167 are preferable, and compounds 2, 38 and 65 are particularly preferable.

The benzophenone derivative (1) is described in JP-A-6-239843 (European Patent Publication 56).
7026) and "DA Walsh, Synthesis 1980, p.677" or a method analogous thereto.

The salts of the benzophenone derivative (1) include hydrochlorides, sulfates, nitrates, bromates, iodates,
Inorganic salts such as borofluoride, perchlorate, etc. and organic salts such as acetate, formate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, tartrate, etc. And so on.

The asymmetric hydrogenation catalyst used for hydrogenating the benzophenone derivative (1) or a salt thereof is preferably a transition metal complex, a base and an optically active nitrogen compound. Specific examples of the transition metal complex include complexes of ruthenium, rhodium, iridium, palladium, platinum and the like of Group 8 of the periodic table, and of these, the ruthenium complex is particularly preferable. Examples of the ruthenium complex include those represented by the following formulas (3) to (6).

[0034]

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(In the formula, X represents a halogen atom, L represents an optically active phosphine ligand, and A represents a tertiary amine.)

[0036]

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(In the formula, X and L have the same meanings as described above, and E represents benzene or p-cymene which may have a substituent.)

[0038]

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(In the formula, L represents the same meaning as described above, and G represents a halogen atom or acetoxy.)

[0040]

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(In the formula, X and L have the same meanings as described above, and J ⁻ is BF ₄ ⁻ , ClO ₄ ⁻ , PF ₆ ⁻ or BPh ₄ ⁻ (P
h represents a phenyl group)

Examples of the halogen atom in the above complex include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Of these, chlorine, bromine and iodine are preferable, and chlorine is particularly preferable. Examples of the tertiary amine include tri-lower alkylamine, specifically trimethylamine, triethylamine, tripropylamine and the like, with triethylamine being preferred. Moreover, as the substituent of benzene which may have a substituent, a lower alkyl group having 1 to 4 carbon atoms and 1 to 4 carbon atoms
4 lower alkoxy group, an alkoxycarbonyl group, and a halogen atom are mentioned, and a lower alkyl group having 1 to 4 carbon atoms is particularly preferable. Specific examples of benzene having a substituent include toluene, xylene, trimethylbenzene (especially mesitylene), durene, hexamethylbenzene, ethylbenzene, tert-butylbenzene, and cymene (especially p).
-Cymene), cumene, methyl benzoate, methyl methylbenzoate, methyl chlorobenzoate, anisole, methylanisole, chlorobenzene, dichlorobenzene, trichlorobenzene, bromobenzene, fluorobenzene and the like.

Examples of the complexes (3) to (6) include the following. Complex (3): [Ru ₂ Cl ₄ (L) ₂ ] NEt ₃ , [Ru _{2
Br 4 (L) 2] NEt} 3, [Ru 2 I 4 (L) 2] NEt 3 complex (4): [RuI (p- cymene) (L)] I,
[RuCl (p-cymene) (L)] Cl, [RuBr
(P-cymene) (L)] Br, [RuI (benzene)
(L)] I, [RuCl (benzene) (L)] Cl,
[RuBr (benzene) (L)] Br, [RuI (toluene) (L)], [RuCl (xylene) (L)] C
1, [RuBr (mesitylene) (L)] Br, [RuI
(Hexamethylbenzene) (L)] I complex (5): [RuBr ₂ (L)], [Ru (OAc) ₂
(L)] complexes (6): [RuCl (L )] + BF 4 -, [RuCl
(L)] ⁺ ClO ₄ ⁻ , [RuCl (L)] ⁺ PF ₆ ⁻ , [R
uCl (L)] ⁺ BPh ₄ ^-

Among the above complexes (3) to (6), the complexes (3) and (4) are preferable, and the complex (3) is particularly preferable.

In the above complex, L represents an optically active phosphine ligand, and specific examples thereof include compounds represented by the following general formula (7) or (8).

[0046]

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(In the formula, R ¹² represents a lower alkyl group having 1 to 4 carbon atoms, and R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different and each is a hydrogen atom or carbon number. A lower alkyl group having 1 to 4 or a lower alkoxy group having 1 to 4 carbon atoms, a halogen atom, or R ¹⁴ and R ¹⁵ , R ¹⁶ and R ¹⁷ may be bonded to each other to form a ring)

[0048]

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(In the formula, R ¹⁹ represents a hydrogen atom or a carbon number of 1 to 4)
Represents a lower alkyl group of

In the above ligands (7) and (8), R
Examples of the lower alkyl group having ^{12 to} R ¹⁹ and having 1 to 4 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group and n-
Examples thereof include a butyl group, an isobutyl group and a tert-butyl group, and a methyl group is particularly preferable. Substituted carbon number 1 to
Examples of the lower alkoxy group of 4 include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, an n-butyloxy group, an isobutyloxy group and a tert-butyloxy group, and a methoxy group is particularly preferable. Examples of the halogen atom as a substituent include fluorine, chlorine, bromine and iodine, with chlorine and bromine being particularly preferable.

In the ligand (7), R ¹⁴ and R ¹⁵ , R ¹⁶
And R ¹⁷ may combine with each other to form a ring, for example, a group —CH═CH—CH═CH—, a group — (CH ₂ ) ₄ — and the like to form a 6-membered ring.

Specific examples of the ligand (7) include optically active phosphine ligands represented by the following general formulas (9) and (10).

[0053]

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(In the formula, R ¹² has the same meaning as described above,
R ²⁰ and R ²¹ each represent a hydrogen atom or a methyl group,
Alternatively, R ²⁰ and R ²¹ are bonded together to form a group —CH═CH—C.
H = CH- may be formed)

[0055]

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(In the formula, R ¹² has the same meaning as described above)

Regarding the position of the substituent of the substituted phenyl bonded to the phosphorus atom of the optically active phosphine ligand as described above, the groups -R ¹² of the ligands (7), (9) and (10) are used. In addition, those substituted at the meta position are preferable, and by selecting this position, the target compound having good optical purity (% ee) can be obtained.

As the optically active phosphine ligand, there are a binaphthyl skeleton such as the ligand (9) and an octahydrobinaphthyl skeleton such as the ligand (8). Preferred is that by using this, the reaction conversion rate and optical purity (% ee)
It is possible to obtain a target compound having good Therefore, as the optically active phosphine ligand, those having a phenyl group having a substituent at the meta position and a binaphthyl skeleton are most preferable.

The above ligands (7) to (10) can be synthesized by a known method. For example, R ¹⁴ , R ¹⁵ , R ¹⁶
With respect to the biphenyl type optically active ligand (7) in which R ¹⁷ and R ¹⁷ do not form a ring, as described in JP-A-59-65051, they are reacted according to the following reaction formula and optically resolved. Can be obtained by

[0060]

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(Wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ ,
R ¹⁷ and R ¹⁸ have the same meanings as described above, D represents a leaving group, and compound (12) is a compound in which two substituted phenyl groups are substituted on the phosphorus atom.)

That is, 2,2'-lithium-1,1 '
The ligand (7) can be obtained by reacting the biphenyl compound (11) with the di (3,5-disubstituted phenyl) phosphine compound (12) and optically resolving the obtained compound.

The ligand (8) and the ligand (10) can be synthesized, for example, according to the following reaction formula, as described in JP-A-4-139140.

[0064]

[Chemical 21]

(In the formula, R ¹⁹ has the same meaning as described above,
X ¹ and X ² each represent a halogen atom)

That is, 2,2'-halogeno-1,1 '
-Binaphthyl (13) is hydrogenated in the presence of a ruthenium-carbon catalyst to give 2,2'-halogeno-5,5 ', 6.
6 ', 7,7', 8,8'-octahydro-1,1'-
Binaphthyl (14) is reacted with magnesium metal to obtain Grignard reagent (15), which is condensed with diphenylphosphinohalide compound (16) or (17) to obtain a compound, which is optically resolved. The order (8) or (10) can be obtained.

As described above, as the optically active phosphine ligand, the ligand (7) or (8) is preferable, and the ligand (9) of the ligands (7) is particularly preferable, The ligand (10) of the ligand (8) and the ligand (7) is preferable.

The ligand (7) is roughly classified into a biphenyl type ligand in which R ¹⁴ and R ¹⁵ , and R ¹⁶ and R ¹⁷ do not form a ring, and a ring forming ligand. The ligands forming are preferred. Examples of the ligand forming the ring include ligands (9) and (10), and the ligand (9) is particularly preferable.

Specific examples of the biphenyl type ligand (7) in which R ¹⁴ and R ¹⁵ and R ¹⁶ and R ¹⁷ do not form a ring in the ligand (7) include 6,6′-dimethyl-2, 2'-bis (di (3,5-dimethylphenyl) phosphino) -1,
1'-biphenyl, 6,6'-dimethoxy-2,2'-
Bis (di (3,5-dimethylphenyl) phosphino)-
1,1'-biphenyl etc. are mentioned.

Examples of the ligand (9) in which R ¹⁴ and R ¹⁵ and R ¹⁶ and R ¹⁷ form a ring in the ligand (7) include 2,2′-
Bis (di (3,5-dimethylphenyl) phosphino)-
2, such as 1,1′-binaphthyl (DM-BINAP)
2'-bis (di (3,5-di-lower alkylphenyl) phosphino) -1,1'-binaphthyl;7,7'-dimethyl-2,2'-bis (di (3,5-dimethylphenyl)
7,7′-dimethyl-2,2′-bis (di (3,5-dilower alkylphenyl) phosphino) -1,1′-binaphthyl such as phosphino) -1,1′-binaphthyl;
8,8'-Dimethyl-2,2'-bis (di (3,5-dimethylphenyl) phosphino) -1,1'-binaphthyl and other 8,8'-dimethyl-2,2'-bis (di (3,3 5-di-lower-alkylphenyl) phosphino) -1,1′-binaphthyl; and 3,3′- such as 3,3′-bis (di (3,5-dimethylphenyl) phosphino) -4,4′-biphenanthryl. Bis (di (3,5-di-lower alkylphenyl) phosphino) -4,4'-biphenanthryl may be mentioned, and 2,2'-bis (di (3,5-di-lower alkylphenyl) phosphino) -1,1 '-Binaphthyl is preferable, and of these, 2,2'-bis (di (3,5-dimethylphenyl) phosphino) -1,1'-binaphthyl (DM-BINAP) is particularly preferable. The lower alkyl referred to herein means a lower alkyl group having 1 to 4 carbon atoms.

Ligand (8), and ligand (10) in which R ¹⁴ and R ¹⁵ , and R ¹⁶ and R ¹⁷ in the ligand (7) form a ring.
As 2,2'-bis (diphenylphosphino)-
5,5 ', 6,6', 7,7 ', 8,8'-octahydro-1,1'-binaphthyl (OcH-BINAP),
2,2'-bis (di (p-tolyl) phosphino) -5,
5 ', 6,6', 7,7 ', 8,8'-octahydro-
1,1'-Binaphtyl (OcH-Tol-BINAP)
And 2,2'-bis (di (3,5-dimethylphenyl))
Phosphino) -5,5 ', 6,6', 7,7 ', 8,
8'-octahydro-1,1'-binaphthyl (OcH-
2,2′-bis (di (3,5-) such as DM-BINAP)
Di-lower alkylphenyl) phosphino) -5,5 ′,
6,6 ′, 7,7 ′, 8,8′-octahydro-1,
1'-binaphthyl and the like, of which OcH-B
INAP and 2,2'-bis (di (3,5-dilower alkylphenyl) phosphino) -5,5 ', 6,6',
7,7 ', 8,8'-Octahydro-1,1'-binaphthyl is preferred. The lower alkyl referred to here means
It represents a lower alkyl group having 1 to 4 carbon atoms.

Each of these ligands has a (R) -form and a (S) -form, but these can be appropriately selected depending on the target compound. Further, it is also possible to use an optically active phosphine ligand other than the above as shown below.

2,2'-bis (diphenylphosphino)
-1,1'-Binaphtyl (BINAP), 2,2'-bis (di (p-tolyl) phosphino) -1,1'-binaphthyl (Tol-BINAP), 2,2'-bis (dicyclohexylphosphino) -6,6'-dimethyl-1,
1'-binaphthyl (BICHEP), 1- (1,2-bis (diphenylphosphino) ferrocenyl) N, N-dimethylethylamine (BPPFA), 2,3-bis (diphenylphosphino) butane (CHIRAHOS), 1
-Cyclohexyl-1,2-bis (diphenyl) phosphinoethane (CYCPHOS), 1-substituted-3,4-bis (diphenyl) phosphinopyrrolidine (DEGPHO)
S), (R, R) -2,3-o-isopropylidene-
2,3-dihydroxy-1,4-bis (diphenylphosphino) butane (DIOP), (R, R) -1,2-bis [(o-methoxyphenyl) phenylphosphino] ethane (DIPAMP), substituted- 1,2-bis (phosphorano) benzene (DUPHOS), (R, R) -5,6-
Bis (diphenylphosphino) -2-norbornene (N
ORPHOS), N, N'-bis (diphenylphosphino) -N, N'-bis [(R) -1-phenylethyl]
Ethylenediamine (PNNP), (S) -1,2-bis (diphenylphosphino) propane (PROPHO
S), (S, S) -2,4-bis (diphenylphosphino) pentane (SKEWPHOS)

More specific examples of the transition metal complex used in the present invention
As an example, [Ru_TwoCl_Four(DM-BINAP)_Two]
NEt_Three, [Ru_TwoCl_Four(OcH-BINAP)_Two] NE
t_Three, [Ru_TwoCl_Four(OcH-DM-BINAP)_Two] N
Et_Three, [RuI (p-Cymen) (DM-BINA
P)] I, [RuCl (p-cymene) (DM-BIN
AP)] Cl, [RuBr (p-cymene) (DM-B
INAP)] Br, [RuI (benzene) (DM-BI
NAP)] I, [RuCl (benzene) (DM-BIN
AP)] Cl, [RuBr (benzene) (DM-BIN
AP)] Br, [RuI (p-cymene) (OcH-B
INAP)] I, [RuCl (p-cymene) (OcH
-BINAP)] Cl, [RuBr (p-cymene)
(OcH-BINAP)] Br, [RuI (benzene)
(OcH-BINAP)] I, [RuCl (benzene)
(OcH-BINAP)] Cl, [RuBr (benze
(OcH-BINAP)] Br, [RuI (p-sa
Imene) (OcH-DM-BINAP)] I, [RuC
l (p-cymen) (OcH-DM-BINAP)] C
1, [RuBr (p-cymene) (OcH-DM-BI
NAP)] Br, [RuI (benzene) (OcH-DM
-BINAP)] I, [RuCl (benzene) (OcH
-DM-BINAP)] Cl, [RuBr (benzene)
(OcH-DM-BINAP)] Br, [RuBr
_Two(DM-BINAP)], [RuBr_Two(OcH-BI
NAP)], [RuBr_Two(OcH-DM-BINA
P)], [Ru (OAc)_Two(DM-BINAP)],
[Ru (OAc)_Two(OcH-BINAP)], [Ru
(OAc)_Two(OcH-DM-BINAP)], [Ru
Cl (DM-BINAP)]⁺BF_Four ^-, [RuCl (O
cH-BINAP)]⁺BF_Four ^-, [RuCl (OcH-
DM-BINAP)]⁺BF_Four ^-, [RuCl (DM-B
INAP)]⁺ClO_Four ^-, [RuCl (OcH-BIN
AP)]⁺ClO_Four ^-, [RuCl (OcH-DM-BI
NAP)]⁺ClO_Four ^-, [RuCl (DM-BINA
P)]^-PF ₆ ^-, [RuCl (OcH-BINAP)]⁺
PF₆ ^-, [RuCl (OcH-DM-BINAP)]⁺
PF₆ ^-And the like.

Of these, the preferable one is [Ru ₂
Cl ₄ (DM-BINAP) ₂ ] NEt ₃ , [Ru ₂ Cl ₄
(OcH-BINAP) ₂ ] NEt ₃ , [Ru ₂ Cl ₄ (O
cH-DM-BINAP) ₂ ] NEt ₃ , [RuI (p-
(DM-BINAP)] I, [RuCl (p
-Cymene) (DM-BINAP)] Cl, [RuBr
(P-cymen) (DM-BINAP)] Br, [Ru
I (benzene) (DM-BINAP)] I, [RuCl
(Benzene) (DM-BINAP)] Cl, [RuBr
(Benzene) (DM-BINAP)] Br, [RuI
(P-cymen) (OcH-BINAP)] I, [Ru
Cl (p-cymene) (OcH-BINAP)] Cl,
[RuBr (p-cymen) (OcH-BINAP)]
Br, [RuI (benzene) (OcH-BINAP)]
I, [RuCl (benzene) (OcH-BINAP)]
Cl, [RuBr (benzene) (OcH-BINA
P)] Br, [RuI (p-cymene) (OcH-DM
-BINAP)] I, [RuCl (p-cymene) (O
cH-DM-BINAP)] Cl, [RuBr (p-cymene) (OcH-DM-BINAP)] Br, [Ru
I (benzene) (OcH-DM-BINAP)] I,
[RuCl (benzene) (OcH-DM-BINA
P)] Cl, [RuBr (benzene) (OcH-DM-
BINAP)] Br. Particularly preferred _{are, [Ru 2 Cl 4 (DM} -BINAP) 2] NEt 3,
[Ru ₂ Cl ₄ (OcH-BINAP) ₂ ] NEt ₃ , [R
_{u 2 Cl 4 (OcH-DM} -BINAP) 2] NEt 3 and the like.

The amount of the transition metal complex used in the present invention is
Although it varies depending on the reaction vessel, the type of reaction or the economy, the molar ratio to the reaction substrate, benzophenone derivative (1), is 1/100 to 1 / 100,000, preferably 1/500 to 1 / 10,000. It can be used in a range of.

The base used for the asymmetric hydrogenation catalyst in the present invention is, for example, a compound represented by the general formula (18)

[0078]

Embedded image

(Wherein M represents an alkali metal atom or an alkaline earth metal atom, Y represents a hydroxy group, an alkoxy group or a mercapto group, and n is 1 or 2) or a quaternary ammonium salt. And the like, and is not particularly limited, but the compound MY is particularly preferable.

Examples of the alkali metal atom in the base (18) include lithium, sodium, potassium, rubidium and cesium, with sodium and potassium being preferred, and potassium being particularly preferred. Alkaline earth metal atoms include magnesium, calcium, strontium,
Examples include barium, with calcium being preferred. Further, among the alkali metal atom and the alkaline earth metal atom, the alkali metal atom is preferable.

The alkoxy group is an alkoxy group having 1 to 4 carbon atoms, such as methoxy group, ethoxy group, propoxy group, isopropyloxy group, n-butyloxy group,
Examples thereof include a tert-butyloxy group, and a methoxy group, an isopropyloxy group and a tert-butyloxy group are preferable.

Specific examples of the base (18) include potassium hydroxide, sodium hydroxide, cesium hydroxide, methoxylithium, methoxysodium, methoxypotassium, ethoxylithium, ethoxysodium, ethoxypotassium, propoxylithium, propoxysodium and propoxy. Examples thereof include potassium, isopropyloxylithium, isopropyloxysodium, isopropyloxypotassium, tert-butyloxypotassium, and sodium methylmercapto. Sodium hydroxide, potassium hydroxide, isopropyloxypotassium, and tert-butyloxypotassium are preferable, and water is particularly preferable. Potassium oxide and tert-butyloxypotassium are preferred.

The amount of the base used is 0.001 with respect to the benzophenone derivative (1) which is the reaction substrate.
~ 0.5 molar equivalents can be used, but preferably 0.01 to 0.5 molar equivalents, more preferably 0.03.
~ 0.1 molar equivalent.

The optically active nitrogen compound used for the asymmetric hydrogenation catalyst is preferably an optically active amine, specifically, an optically active diamine compound, and further, a carbon atom to which two amino groups and / or substituted amino groups are bonded. Are more preferably adjacent to each other (ethylenediamine type). Further, an optically active diamine compound in which one or two carbon atoms to which an amino group and / or a substituted amino group is bonded is an asymmetric carbon atom is preferable.
An optically active diamine compound having one is more preferable. Examples thereof include ethylenediamine compounds, propanediamine compounds, butanediamine compounds, cyclic hydrocarbon diamine compounds, and phenylenediamine compounds.

Specifically, for example, the following general formula (19)

[0086]

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(Wherein R ²² , R ²³ , R ²⁴ and R ²⁵ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group, an aryl group or a cycloalkyl group having 5 to 7 carbon atoms, or ,
R ²³ and R ²⁴ may combine with each other to form a ring,
²⁶ , R ²⁷ , R ²⁸ and R ²⁹ represent a hydrogen atom, an unsaturated hydrocarbon group, an aryl group or a sulfonyl group. However, R ²² and R
²³ , and R ²⁴ and R ²⁵ are not the same group at the same time. The optically active diamine compound (19) represented by

Substituent of optically active diamine compound (19)
R^{twenty two}, R^{twenty three}, R^{twenty four}, R^{twenty five}, R²⁶, R ²⁷, R²⁸And R²⁹To
In addition, the alkyl group having 1 to 4 carbon atoms is methyl
Group, ethyl group, propyl group, isopropyl group, tert
-Butyl group and the like are mentioned, and a methyl group is particularly preferable.
Aryl groups include phenyl groups, substituted phenyl groups, and
Examples thereof include a futyl group and a substituted naphthyl group, a phenyl group,
Substituted phenyl groups are preferred, and phenyl groups are particularly preferred.
Yes. As the substituted phenyl group, p-tolyl group, 3,5-
Lower alkyl having 1 to 4 carbon atoms such as dimethylphenyl group
A phenyl group having a substituted group, particularly a p-tolyl group
Is preferred. As a cycloalkyl group having 5 to 7 carbon atoms
Is a cyclopentyl group, a cyclohexyl group, a cyclohep
Examples thereof include a tyl group, and a cyclohexyl group is preferable. R^{twenty three}
And R^{twenty four}May combine together to form a ring, but this
Examples of the ring include cyclohexyl ring and cycloheptane ring.
No. As the unsaturated hydrocarbon group, an allyl group, etc.
The chain unsaturated hydrocarbon group of is mentioned.

Specific examples of the nitrogen compound used for the asymmetric hydrogenation catalyst include, for example, 1,2-diphenylethylenediamine, 1,2-dicyclohexylethylenediamine,
2,3-diaminobutane, 1,2-diaminocyclohexane, 1,2-diaminocycloheptane, 1-methyl-
2,2-diphenylethylenediamine, 1-isobutyl-2,2-diphenylethylenediamine, 1-isopropyl-2,2-diphenylethylenediamine, 1-methyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-isobutyl- 2,2-di (p-methoxyphenyl) ethylenediamine, 1-isopropyl-2,2-
Di (p-methoxyphenyl) ethylenediamine, 1-benzyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-methyl-2,2-dinaphthylethylenediamine, 1-isobutyl-2,2-dinaphthylethylenediamine, Examples thereof include 1-isopropyl-2,2-dinaphthylethylenediamine, and 1,2-diphenylethylenediamine is particularly preferable.

Further, the optically active diamine compound (1
In 9), when two of the carbon atoms bonded to the amino group and / or the substituted amino group are asymmetric carbon atoms,
(R, R) -body, (S, S) -body, (R, S) -body,
Four types of isomers of (S, R) -form are conceivable, and among these, (R, R) -form and (S, S) -form are preferable, and these are appropriately selected and used according to the purpose. be able to.

In selecting this isomer, the combination with the optically active phosphine ligand in the transition metal complex used is important. There are various possible cases of this combination, and the (R) -form optically active phosphine ligand and (R,
R) -form optically active amine compound in combination, and (S) -form optically active phosphine ligand and (S, S)-
The combination of the body with the optically active amine compound is the best combination and is important for obtaining a high asymmetric yield.

The optically active nitrogen compound can be used in an amount of 1 to 20 molar equivalents, preferably 4 to 12 molar equivalents, based on the transition metal complex.

The three components of the transition metal complex, the base and the optically active nitrogen compound used as the catalyst in the present invention are essential components for the smooth progress of the asymmetric hydrogenation reaction and the achievement of a high asymmetric yield. Therefore, the optically active benzhydrol derivative having sufficient optical activity and high optical purity can be obtained only when these three components are combined.

The solvent used for hydrogenating the benzophenone derivative (1) or a salt thereof can be used without particular limitation as long as it can solubilize the reaction raw materials and the catalyst system. For example, aromatic hydrocarbon solvents such as toluene and xylene; aliphatic hydrocarbon solvents such as heptane and hexane;
Halogen-containing hydrocarbon solvent such as methylene chloride; ether solvent such as diethyl ether and tetrahydrofuran; alcohol solvent such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol; acetonitrile; DMF (dimethylformamide), DMSO
Examples thereof include organic solvents containing a hetero atom such as (dimethyl sulfoxide). These solvents can be used alone or as a mixed solvent, but since the product is an alcohol, an alcohol solvent is preferable, and 2-propanol is particularly preferable.

The amount of the solvent used is determined by the solubility and economic efficiency of the reaction substrate. For example, in the case of using 2-propanol, the reaction should be carried out depending on the reaction substrate even from a low concentration of 1% by volume or less to a solvent-free state. However, it is preferable to use 2 to 5 times (volume) of the reaction substrate.

The present invention can be carried out in either a batch system or a continuous system. The reaction is carried out in the presence of reactive hydrogen, but the hydrogen pressure is 1 to 10
It can be set to 0 atm, and preferably in the range of 20 to 50 atm. The reaction temperature is preferably 20 to 90 ° C., 35
-60 ° C is particularly preferred. The reaction time is preferably 2 to 48 hours, particularly preferably 16 to 30 hours.

The desired compound (1) obtained as described above can be obtained by known means such as concentration, solvent extraction, fractional distillation,
It can be isolated and purified from the reaction solution by crystallization, recrystallization, chromatography and the like. From the obtained compound (1), a known method, for example, JP-A-6-23984.
By the method described in Japanese Patent Publication No. 3, a pharmaceutical useful as a squalene synthase inhibitor or a triglycerin lowering agent can be produced.

[0098]

The present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the invention thereto. The following instruments were used to measure each spectrum in the examples.

¹ H nuclear magnetic resonance spectrum ( ¹ H-NMR): AM
-400 type (manufactured by Bruker) Internal reference material: tetramethylsilane Solvent: CDCl ₃ mass spectrum (MS): M-80B mass spectrometer (manufactured by Hitachi, Ltd.)

The reaction conversion rate and optical purity of the products in each example were confirmed by high performance liquid chromatography (HPLC) under the following conditions.・ Reaction conversion high performance liquid chromatography: HITACHI L-4000 Column: INERTSIl ODS 4.6 × 250 mm Developing solvent: Acetonitrile / H ₂ O (volume ratio 90/10) Wavelength: 254 nm Temperature: Room temperature: 0.5 ml / min ・ Optical Purity High Performance Liquid Chromatography: HITACHI 655A Column: CIRAL CEL OD-H 4.6 × 250 mm Developing solvent: Hexane / 2-propanol (Volume ratio 80/20
) Wavelength: 254 nm Temperature: Room temperature Flow: 1 ml / min

Example 1 Into a 10-liter stainless steel autoclave, 85% potassium hydroxide (11.88 g, 0.18 mol) 2-
Add propanol solution (3375 ml), (1S, 2
S) -1,2-diphenylethylenediamine (2.18
g, 10.27 mmol), 2-amino-5-chloro-
2 ', 3'-dimethoxybenzophenone (1500 g,
5.142 mol), tetrahydrofuran (THF)
(1125 ml), and Ru ₂ Cl ₄ ((S) -DM-B
INAP) ₂ NEt ₃ (1.64g, 0.8564mmo
1) was inserted under a nitrogen atmosphere, and then hydrogen gas was injected up to 40 atm. The reaction temperature was 43 ° C., the mixture was stirred for 30 hours, then returned to room temperature, and the optical purity of the product was measured by high performance liquid chromatography (HPLC).
It was 3.9% ee.

The residue obtained by concentrating the reaction solution under reduced pressure was mixed solvent 6 of ethyl acetate / hexane = 1/1 (volume ratio).
Recrystallization was performed in liter to obtain (S) -2-amino-5-chloro-2 ′, 3′-dimethoxybenzhydrol 14
02 g (yield 92.8%) was obtained. The optical purity of this product was measured by high performance liquid chromatography.
It was 9.9% ee or more.

M. p. 137.8-138.5 ° C ¹ H-NMR (400 MHz, CDCl ₃ , δppm):
3.30 (d, J = 5.0 Hz, 1H), 3.80
(S, 3H), 3.86 (s, 3H), 4.17 (br
oads, 2H), 6.01 (d, J = 5.0 Hz,
1H), 6.54 (d, J = 8.4 Hz, 1H), 6.
87 (s, 1H), 6.89 (s, 1H), 6.99-
7.08 (m, 4H) MS (m / e): 293 (M +)

Example 2 In a 100 ml stainless steel autoclave, a 0.2 M solution of potassium hydroxide in 2-propanol (1.
2 ml, 0.24 mmol of potassium hydroxide), (1
S, 2S) -1,2-Diphenylethylenediamine (2.9 mg, 0.0137 mmol), 2-amino-
5-chloro-2 ′, 3′-dimethoxybenzophenone (2 g, 6.86 mmol), 2-propanol (3.
3 ml), THF (1.5 ml), and Ru ₂ Cl
₄ ((S) -DM-BINAP) ₂ NEt ₃ (6.56 m
g, 0.00343 mmol) under a nitrogen atmosphere and then hydrogen gas was introduced up to 50 atm. After stirring at a reaction temperature of 50 ° C. for 20 hours, the reaction solution was returned to room temperature and concentrated under reduced pressure.

2.13 g of the obtained residue was purified by silica gel column chromatography (developing solution: hexane / ethyl acetate = 4/1 to 2/1 (volume ratio)) to obtain (S) -2.
1.96 g (yield 97.3%) of -amino-5-chloro-2 ', 3'-dimethoxybenzhydrol was obtained. The optical purity of this product was measured by high performance liquid chromatography and found to be 94.2% ee.

Example 3 A 0.2 M solution of potassium hydroxide in 2-propanol (6.
0 ml, potassium hydroxide 1.2 mmol), (1S,
2S) -1,2-diphenylethylenediamine (14.
55 mg, 0.0686 mmol), 2-amino-5-
Chloro-2 ', 3'-dimethoxybenzophenone (5.
00 g, 17.14 mmol), 2-propanol (1
2.75 ml), benzene (1.25 ml), and Ru
₂ Cl ₄ ((S) -OcH-DM-BINAP) ₂ NEt ₃
(33.1 mg, 0.017 mmol) was inserted under a nitrogen atmosphere, and hydrogen gas was introduced under pressure up to 50 atm. After stirring at a reaction temperature of 50 ° C. for 24 hours, the reaction solution was returned to room temperature. The reaction conversion rate and optical purity were measured by high performance liquid chromatography to be 98.0% and 8 respectively.
It was 8.9% ee.

The reaction mixture was concentrated under reduced pressure to obtain the residue 5.
37 g was recrystallized with ethyl acetate to obtain 3.50 g (yield 69.5%) of (S) -2-amino-5-chloro-2 ′, 3′-dimethoxybenzhydrol. The optical purity of this product was 99.9% ee or higher as measured by high performance liquid chromatography.

Example 4 0.2M was added to a 100 ml stainless steel autoclave.
The prepared 2-propanol solution of potassium hydroxide (0.
6 ml, potassium hydroxide 0.12 mmol), (1
S, 2S) -1,2-Diphenylethylenediamine
(2.9 mg, 0.0137 mmol), 2-amino-
5-chloro-2 ', 3'-dimethoxybenzophenone
(1.00 g, 3.43 mmol), 2-propanol
(3.15 ml), benzene (1.25 ml), and R
u_TwoCl_Four((S) -OcH-BINAP) _TwoNEt
_Three(5.85 mg, 0.00343 mmol) in a nitrogen atmosphere.
Insert at ambient pressure, then pressurize hydrogen gas to 50 atm
Was. After stirring at a reaction temperature of 50 ° C. for 20 hours, the reaction liquid
Was concentrated under reduced pressure.

1.04 g of the obtained residue was purified by silica gel column chromatography (developing solution: hexane / ethyl acetate = 4/1 to 2/1 (volume ratio)) to obtain (S) -2.
0.98 g (yield 97.3%) of -amino-5-chloro-2 ', 3'-dimethoxybenzhydrol was obtained. The optical purity of this product was measured by high performance liquid chromatography and found to be 71.9% ee.

Example 5 In a 100 ml stainless steel autoclave, a 0.2 M solution of potassium hydroxide in 2-propanol (3.
5 ml, 0.709 mmol of potassium hydroxide), (1
R, 2R) -1,2-Diphenylethylenediamine (8.6 mg, 0.0405 mmol), 2-amino-
2 ', 5-dichlorobenzophenone (2.66 g, 1
0.0 mmol), 2-propanol (6.5 ml),
Benzene (3.3 ml), and Ru ₂ Cl ₄ ((R) -D
M-BINAP) ₂ NEt ₃ (19.5 mg, 0.010)
(13 mmol) was inserted under a nitrogen atmosphere, and then hydrogen gas was introduced up to 50 atm. 20 at a reaction temperature of 50 ° C
After stirring for an hour, the reaction solution was concentrated under reduced pressure.

2.68 g of the obtained residue was purified by silica gel column chromatography (developing solution: hexane / ethyl acetate = 4/1 to 2/1 (volume ratio)) to give oily (R) -2-amino. 2.60 g (yield 97.0%) of -2 ', 5-dichlorobenzhydrol was obtained. The optical purity of this product was measured by high performance liquid chromatography and found to be 79.9% ee.

¹ H-NMR (400 MHz, CDCl ₃ ,
δppm): 2.66 (d, J = 3.8Hz, 1H),
4.05 (broads, 2H), 6.15 (d, J
= 3.8 Hz, 1H), 6.62 (d, J = 8.4H)
z, 1H), 6.89 (d, J = 2.5Hz, 1H),
7.07 (dd, J = 2.5 Hz, 8.4 Hz, 1
H), 7.29 to 7.48 (m, 4H) MS (m / e): 267 (M ⁺ ).

Examples 6 and 7 Reactions were carried out in the same manner as in Example 5 except that the starting compounds were changed as shown in Table 8 to obtain (R) -form hydrides. Table 8 shows the results.

[0114]

[Table 8]

Example 8 A 2-propanol solution of potassium hydroxide (0.2 M) prepared in 0.2 M was added to a 100 ml stainless steel autoclave.
6 ml, potassium hydroxide 0.12 mmol), (1
R, 2R) -1,2-Diphenylethylenediamine (2.9 mg, 0.0137 mmol), 2-amino-
5-chloro-2 ', 3'-dimethoxy benzophenone (1.00 g, 3.43 mmol), 2-propanol (6.9 ml), benzene (2.5 ml), and Ru ₂
Cl ₄ ((R) -Tol-BINAP) ₂ NEt ₃ (6.
(18 mg, 0.00343 mmol) was introduced under a nitrogen atmosphere, and then hydrogen gas was injected up to 50 atm. After stirring at a reaction temperature of 50 ° C. for 18 hours, the reaction solution was returned to room temperature. The reaction conversion rate measured by high performance liquid chromatography was 90.9%.

The reaction solution was concentrated under reduced pressure, and 1.05 g of the obtained residue was purified by silica gel column chromatography (developing solution: hexane / ethyl acetate = 4/1 to 2/1 (volume ratio)) to give an oil. (R) -2-amino-5-chloro-2 ′, 3′-dimethoxybenzhydrol was added to 0.8
5 g (yield 84.4%) was obtained. The optical purity of this product was measured by high performance liquid chromatography to be 57.4.
% Ee.

Example 9 A transition metal complex was added to Ru ₂ Cl ₄ ((R) -BINAP) ₂ N.
The reaction was performed in the same manner as in Example 8 except that Et ₃ was used, and (R) -2-amino-5-chloro-2 ′, 3′-dimethoxybenzhydrol was obtained in a yield of 96.2% and had an optical purity. Obtained with 61.6% ee.

Comparative Example 1 The reaction was performed in the same manner as in Example 5 except that 4-aminobenzophenone was used as the starting compound, and (R) -4-aminobenzohydrol was obtained in a yield of 99.32% and an optical purity of 20. ．
Obtained with 44% ee.

[0119]

INDUSTRIAL APPLICABILITY As described above, the production method of the present invention is industrially advantageous in that an optically active benzhydrol derivative useful as a pharmaceutical synthesis intermediate or the like can be produced in a high purity by a simple operation. It is a manufacturing method.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location // C07B 61/00 300 C07B 61/00 300 C07M 7:00 (72) Inventor Takashi Miura Nishi Hiratsuka, Kanagawa Prefecture Hachiman 1-chome 4-11 Takasago Fragrance Industry Co., Ltd. Research Institute (72) Inventor Tetsuro Yamazaki 1-4-11 Nishihachiman, Hiratsuka-shi, Kanagawa Takasago Fragrance Industry Co., Ltd. (72) Inventor Taiichi Okada Kyoto Prefecture 380 Tsuchihashi-cho, Fushimi-ku, Kyoto

Claims (14)

[Claims] 1. The following general formula (1): (In the formula, R represents an amino group which may have a substituent, and A ring and B ring may each further have a substituent), and a benzophenone derivative or a salt thereof is represented by an asymmetric hydrogen. Of the following general formula (2) characterized by hydrogenation in the presence of a oxidization catalyst: (In the formula, R, A ring and B ring have the same meanings as described above,
* Indicates the position of the asymmetric carbon), and a method for producing an optically active benzhydrol derivative or a salt thereof. 2. The production method according to claim 1, wherein the asymmetric hydrogenation catalyst comprises a transition metal complex, a base and an optically active nitrogen compound. 3. The production method according to claim 1, wherein R is an amino group, or a lower alkyl group, an acyl group or a protecting group is a mono-substituted amino group. 4. The ring A and ring B substituents are halogen atoms,
Hydroxy group, optionally halogenated carbon number 1
4 alkyl groups, optionally halogenated 1 carbon atoms
1-4 alkoxy groups, alkanoyl groups having 1-5 carbon atoms, and alkyl groups having 1-4 carbon atoms are 1-4 selected from the group consisting of optionally substituted amino groups.
The manufacturing method according to any one of 3 above. 5. The production method according to claim 4, wherein the substituent on the ring A is two optionally halogenated alkoxy groups having 1 to 4 carbon atoms. 6. The method according to claim 4, wherein the ring B has 1 or 2 halogen atoms. 7. The production method according to claim 2, wherein the transition metal complex is a ruthenium complex. 8. A ruthenium complex having the following general formula (3):
(4), (5) or (6) (In the formula, X represents a halogen atom, L represents an optically active phosphine ligand, and A represents a tertiary amine.) (In the formula, X and L have the same meanings as described above, and E represents benzene optionally having a substituent or p-cymene.) (In the formula, L represents the same meaning as described above, and G represents a halogen atom or acetoxy.) (In the formula, X and L have the same meanings as described above, and J ⁻ is BF _{4
^{-, ClO 4 -, PF 6}} - or BPh ₄ ^- (Ph represents a phenyl group) The method according to claim 7, wherein is represented by showing a). 9. The optically active phosphine ligand has the following general formula:
(7) [Chemical 7](Where R¹²Represents a lower alkyl group having 1 to 4 carbon atoms,
R¹³, R¹⁴, R^Fifteen, R¹⁶, R¹⁷And R¹⁸Are the same
Or differently, a hydrogen atom or a lower alkyl having 1 to 4 carbon atoms
Groups, lower alkoxy groups having 1 to 4 carbon atoms, halogen atoms
Show or R¹⁴And R ^Fifteen, R¹⁶And R¹⁷Are combined
An optically active phosphine represented by (may form a ring)
The method according to claim 8, which is a ligand. 10. The optically active phosphine ligand has the following general formula (8): The production method according to claim 8, which is an optically active phosphine ligand represented by the formula: wherein R ¹⁹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms. 11. The optically active phosphine ligand is 2,2 ′.
9. The method according to claim 8, which is -bis (di (3,5-dilower alkylphenyl) phosphino) -1,1'-binaphthyl. 12. The optically active phosphine ligand is 2,2 ′.
-Bis (diphenylphosphino) -5,5 ', 6
6 ', 7,7', 8,8'-octahydro-1,1'-
Binaphthyl or 2,2'-bis (di (3,5-dilower alkylphenyl) phosphino) -5,5 ', 6,6',
The method according to claim 8, which is 7,7 ', 8,8'-octahydro-1,1'-binaphthyl. 13. The base has the following general formula (18): (Wherein M represents an alkali metal atom or an alkaline earth metal atom, Y represents a hydroxy group, an alkoxy group or a mercapto group, and n is 1 or 2) or a quaternary ammonium salt. The manufacturing method according to claim 2. 14. The method according to claim 2, wherein the optically active nitrogen compound is an optically active amine.