JP3450386B2 - Method for producing optically active γ-hydroxy ketones - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an optically active γ-hydroxyketone which can be used as an intermediate for producing an optically active tetrahydrofuran useful as an optically active moiety such as a pharmaceutical intermediate, a biodegradable polymer and a fragrance. Regarding

[0002]

BACKGROUND OF THE INVENTION Optically active γ-hydroxyketones can be converted into optically active tetrahydrofurans useful as optically active moieties of various compounds by intramolecularly acetalizing them, and thus they can be used as industrial raw materials. is important.

The following two methods are known as methods for synthesizing such optically active γ-hydroxyketones. (I) A method obtained by oxidizing an optically active γ-diol. That is, J. Chem. Soc. Perkin Trans., 2148-2154 (197
(7 years), (2R, 5R) -2,5-hexanediol was oxidized with silver carbonate-celite to give (R) -5-hydroxyhexane.
2-one is obtained with a yield of 46%. (Ii) using chemically modified nickel as a catalyst,
A method for synthesizing an optically active γ-hydroxyketone by asymmetrically hydrogenating a γ-diketone. That is, Bull.Soc.Chem.Belg., 100 , pp. 585-595 (1991).
Asymmetric reduction with 2,5-hexanedione to give (R) -5-hydroxyhexan-2-one 10.1% ee, 78.
Obtained in a yield of 7%.

In the method (i), an optically active γ-diol is used as a starting material. As a method for synthesizing this optically active γ-diol, J. Org. Chem. 54 , 17 is used.
55-1756 (1989), Tetrahedron Asymmetry, 7 (2), 569
Page (1991), Tetrahedron Lett., 28 (50), 6335-6338 (19).
87), Tetrahedron Asymmetry, 3 (3), pp.333-336 (1992)
However, all of them have problems such as long reaction process, low yield, and low optical purity. Also, (ii)
Since the method (2) has too low optical purity, it cannot be industrially adopted.

[0005]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a method for producing optically active γ-hydroxyketones which is simpler, has a smaller number of steps, and has a higher optical purity.

[0006]

Under the circumstances, the present inventors have focused their attention on γ-diketones as a raw material, and have conducted diligent research on this asymmetric hydrogenation reaction. As a result, a relatively inexpensive ruthenium- If asymmetric hydrogenation is carried out using an optically active phosphine complex, γ-
The present invention has been completed by finding that hydroxyketones can be obtained.

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

[0008]

[Chemical 9]

Γ in which R ¹ and R ² represent an optionally substituted alkyl or phenyl group
-The following general formula (2), which is characterized by asymmetric hydrogenation of diketones using a ruthenium-optically active phosphine complex as a catalyst,

[0010]

[Chemical 10]

A method for producing an optically active γ-hydroxyketone represented by the formula (wherein R ¹ and R ² have the same meanings as described above).

In the general formula (1) showing the raw material of the method of the present invention,
The alkyl group represented by R ¹ and R ² has 1 to 1 carbon atoms.
8 are preferable, for example, methyl group, ethyl group, n-
Examples thereof include a propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group and an n-octyl group. Examples of the group capable of substituting for the alkyl group include a phenyl group, an alkoxy group, a halogen atom and the like. Examples of the group that can be substituted on the phenyl group include a lower alkyl group, a lower alkoxy group and a halogen atom.
Here, the carbon number of the lower alkyl group and the lower alkyl group is 1
~ 6 are preferred. Specific examples of the γ-diketones (1) include, for example, 2,5-hexanedione, 2,5-heptanedione, 2,5-octanedione, 2,5-nonanedione, 2,5-decanedione, 2 , 5-Undecanedione, 2,5-Dodecanedione, 2,5-Tridecanedione, 3,6-Octadione, 3,6-Nonanedione, 3,6-Decandione, 4,7-Decandione, 4,
7-dodecanedione, 5,8-undecanedione, 1-phenyl
-1,4-pentanedione, 1-phenyl-1,4-hexanedione, 1-phenyl-1,4-heptanedione, 1-phenyl-1,4-
Octanedione, 1- (p-methoxyphenyl) -1,4-pentanedione, 1- (p-tolyl) -1,4-pentanedione, 1-
Phenyl-2,5-hexanedione, 1-phenyl-2,5-heptanedione, 1-phenyl-2,5-octanedione, 1-phenyl-2,5-nonanedione, 1- (p-methoxyphenyl)- 2,5-
Hexanedione, 1- (p-tolyl) -2,5-hexanedione, 1,6-diphenyl-2,5-hexanedione and the like can be mentioned.

These γ-diketones (1) are described, for example, in Angew. Chem. Int. Ed. Engl., 15 (11), 639-712 (1976).
Year), or by the reaction of an aldehyde and vinyl ketone, or Chem.ber., 118 (3), 1115-1125 (1985).
It can be prepared by the reaction of an α-keto acid and a vinyl ketone as described.

The ruthenium-optically active phosphine complex of the catalyst used in the present invention has the following general formula (3):
The thing represented by (4), (5), and (6) is mentioned.

[0015]

Embedded image Ru _x H _y Cl _z (BIPHOS) ₂ (S) _p (3)

(Where BIPHOS is the expression (a), (b))
Or a tertiary phosphine represented by (c),

[0017]

[Chemical 12]

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R
¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or 1 to 4 carbon atoms.
4 represents an alkoxy group, (S) represents a tertiary amine,
(When y is 0, x is 2, z is 4, and p is 1. When y is 1, x is 1, z is 1, and p is 0.)

[0019]

Embedded image _{[RuA K (B) m (} BIPHOS)] Y n ····· (4)

(In the formula, A represents a halogen atom, B represents benzene or acetonitrile which may have a substituent, Y represents a halogen atom, ClO ₄ , PF ₆ , BPh ₄ or BF ₄ , BIPHOS has the same meaning as described above, and when B is benzene which may have a substituent, k is 1, m is 1,
In the case of n being 1 and acetonitrile, when k is 1, m is 2, when n is 1, and when k is 0, m is 4 and n is 2.
Is)

[0021]

Embedded image [RuI (p-cymene) (BIPHOS)] I ₃ (5) (wherein BIPHOS has the same meaning as described above)

[0022]

Embedded image Ru (OCO—R ¹⁵ ) ₂ (BIPHOS) (6) (In the formula, R ¹⁵ represents a hydrogen atom or a lower alkyl group, and
(IPHOS has the same meaning as above)

Of the above BIPHOS, the tertiary phosphine of formula (a) is particularly preferred. Further, examples of the halogen atom represented by R ^{3 to} R ¹⁴ include a chlorine atom, a bromine atom and a fluorine atom, and among these, a chlorine atom and a fluorine atom are preferable. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, a t-butyl group and the like, and among them, a methyl group and a t-butyl group are preferable. As the alkoxy group having 1 to 4 carbon atoms, a methoxy group,
Examples thereof include an ethoxy group, an n-propyloxy group, and an n-butyloxy group, and among them, a methoxy group is particularly preferable. Further, the lower alkyl group represented by R ¹⁵ is an alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group,
Examples thereof include n-propyl group, t-butyl group, pentyl group and hexyl group.

Further, among the tertiary phosphines of the above formula (a), compounds represented by the following (a-1) are particularly preferable.

[0025]

[Chemical 16]

(In the formula, R ¹⁶ is a hydrogen atom, a methyl group or t
-Represents a butyl group)

The compound of the general formula (3) can be prepared according to J. Chem. Soc.
pp.922-924, (1985), JP-A-61-63690, JP-A-63-135397, or JP-A-4-131940. For example, the complex of the general formula (3) when y = 0 is obtained by reacting ruthenium chloride with cycloocta-1,5-diene (hereinafter abbreviated as COD) in an ethanol solution [RuCl ₂ (COD )] _c
BIPH represented by 1,2'-bis (diphenylphosphino) -1,1'-binaphthyl and 1 molar equivalent (c is a natural number)
It can be obtained by reacting 1.05 to 1.2 molar equivalents of OS in the presence of 4 molar equivalents of a tertiary amine such as triethylamine in a solvent such as toluene or ethanol.

Further, the compound of the general formula (4) is disclosed in JP-A-2-
It can be obtained by the method disclosed in Japanese Patent Laid-Open No. 192189 or Japanese Patent Laid-Open No. 4-139140. For example, a complex in which B is benzene which may have a substituent (hereinafter abbreviated as Ar) can be obtained as follows. For example, when both A and Y are chlorine atoms, that is, [RuCl (Ar) (BIPHOS)] Cl is
J.Org.Chem., 7 , p. 487 (1976), or Can.J.Chem.,
50 , page 3643 (1972). [RuCl ₂ (A
r)] ₂ as a raw material, and this is reacted with BIPHOS in a single solvent such as methanol, ethanol, benzene, and methylene chloride or a mixed solvent thereof at 25 to 50 ° C for 30 minutes to 3 hours, and then the solvent is reduced under reduced pressure. It can be obtained by distilling off at. When both A and Y are bromine atoms or iodine atoms, that is, [RuBr (Ar) (BIPHOS)] Br or [RuI
(Ar) (BIPHOS)] I is obtained by using, for example, [RuCl ₂ (Ar)] ₂ as a raw material,

[0029]

[Chemical formula 17] M ¹ Z ... (7)

(Wherein M ¹ represents a lithium, sodium or potassium atom and Z represents a bromine atom or an iodine atom) is reacted with water as a solvent, or [RuCl 2 ₂ (Ar)] ₂ and M ¹ Z in a solvent of water and methylene chloride, represented by the following general formula (8),

[0031]

Embedded image R ¹⁷ R ¹⁸ R ¹⁹ R ²⁰ QX ... (8)

(Wherein R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ represent an alkyl group having 1 to 16 carbon atoms, a phenyl group or a benzyl group, Q represents a nitrogen atom or a phosphorus atom, and X represents a halogen atom. [RuZ ₂ (Ar)] ₂ is obtained by using a quaternary ammonium salt or a quaternary phosphonium salt represented by the formula) as a phase transfer catalyst and reacting at room temperature. Here, as the phase transfer catalyst (8), for example, the one described in WPWeber, GWGokel, co-translated by Iwao Tabushi, Takako Nishitani, "Phase Transfer Catalyst", Kagaku Dojin Co., Ltd. (1978-9-5), first edition Is used. Then, the obtained [RuZ ₂ (Ar)] ₂ and BIPHOS are reacted in a single solvent such as methanol, ethanol, benzene or methylene chloride or a mixed solvent thereof at 25 to 50 ° C. for 30 minutes to 3 hours. After that, the solvent was distilled off under reduced pressure to quantitatively [RuBr (Ar) (BIPHOS)] Br or [RuI (Ar)
(BIPHOS)] I can be synthesized. Furthermore, for example, A
Is a chlorine atom and Y is ClO ₄ , PF ₆ , BPh ₄ or BF ₄ , then [R
uCl (Ar) (BIPHOS)] Cl is dissolved in methanol, ethanol, acetone, methylene chloride, etc., and M ² Y (where M ² represents sodium, potassium, lithium, magnesium, silver atom, Y Is a halogen atom, ClO ₄ , PF ₆ , BPh
₄ or BF ₄ ) is added and stirred, and then a small amount of insoluble matter is filtered off and the filtrate is concentrated and dried to obtain the target complex [RuA (Ar) (BIPHOS)] Y. it can.

Among the compounds represented by the general formula (4), B
For example, a complex in which A is Y is a chlorine atom in both A and Y, that is, [RuCl (acetonitrile) ₂ (BIP
HOS)] Cl is prepared by dissolving the [RuCl (Ar) (BIPHOS)] Cl complex in acetonitrile and refluxing at 50 ° C. for 10 to 24 hours, distilling off excess acetonitrile, and drying. The [RuCl (acetonitrile) ₂ (BIPHOS)] Cl complex can be obtained by recrystallizing this crude complex from methylene chloride. Further, for example, [RuCl (Ar) (BIPHOS)] Cl complex is dissolved in a mixed solvent of acetonitrile and methanol, ethanol, acetone, methylene chloride or the like, and M ² Y (M ² and Y are the same as above) Is added and the mixture is heated with stirring at 25 to 50 ° C. for 10 to 24 hours, the solvent is distilled off, and dried. By recrystallizing this crude complex with methylene chloride, [Ru (acetonitrile) ₄ (BIPHO
S)] Y ₂ complex can be obtained.

Further, the compound of the general formula (5) is disclosed in
As described in 111639 or JP-A-4-139140, [RuI
The (p-cymene) (BIPHOS)] I complex was obtained by stirring in a suitable solvent such as 3 molar equivalents of iodine and methanol at 15 to 30 ° C for 1 to 5 hours, distilling off the solvent and drying. To be

Further, in the compound of the general formula (6), among the compounds represented by the general formula (3), x is 2, y is 0,
A complex in which z is 2, S is triethylamine, and p is 1, that is, Ru ₂ Cl ₄ (BIPHOS) ₂ (triethylamine)
As a raw material, and this and a carboxylic acid salt in an alcohol solvent such as methanol, ethanol, or t-butanol for about 20 to
After reacting at a temperature of 110 ° C. for 3 to 15 hours, the solvent is distilled off, the target complex is extracted with a solvent such as ether or ethanol, and then dried to obtain a crude complex. Further, a purified product can be obtained by recrystallization with ethyl acetate or the like. In the formula (6), the compound in which R ¹⁵ is a lower alkyl group can be obtained by changing the type of carboxylic acid used. For example, when using the above complex as a raw material and sodium acetate, Ru (OCOCH ₃ ) ₂ (BIPHOS) is obtained. Further, in the case of producing a complex having trifluoroacetic acid, JP-A-62-62
-265293, it can be obtained by reacting the diacetate complex obtained as described above with trifluoroacetic acid in methylene chloride as a solvent at about 25 ° C for about 12 hours.

Examples of the above complex include the following. Ru ₂ Cl ₄ (BINAP) ₂ (NEt ₃ ), (BINAP means 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl) Ru ₂ Cl ₄ (T-BINAP) ₂ (NEt ₃ ), (T-BINAP is 2,2'-bis (di
-p-tolylphosphino) -1,1'-indicates binaphthyl) Ru ₂ Cl ₄ (t-Bu-BINAP) ₂ (NEt ₃ ), (t-Bu-BINAP is 2,2'-bis (di-p -Tert-butyl phenyl phosphino) -1,
1'-indicates binaphthyl) Ru ₂ Cl ₄ (p-MeO-BINAP) ₂ (NEt ₃ ) (p-MeO-BINAP is 2,2'-bis (di-p-methoxyphenylphosphino) -1,1 '-Means binaphthyl) Ru ₂ Cl ₄ (3,5-DiMe-BINAP) ₂ (NEt ₃ ) (3,5-DiMe-BINAP is 2,2'-bis (di-3,5-xylylphos) Fino) means 1,1'-binaphthyl) Ru ₂ Cl ₄ (3,5-Di-t-Bu-BINAP) ₂ (NEt ₃ ) (3,5-Di-t-Bu-BINAP is 2, 2'-bis (di-3,5-di-tert-
Butylphenylphosphino) -1,1'-means binaphthyl) Ru ₂ Cl ₄ (3-Me-BINAP) ₂ (NEt ₃ ) (3-Me-BINAP is 2,2'-bis (di-m- Trilyphosphino)-
Means 1,1'-binaphthyl) Ru ₂ Cl ₄ (p-Cl-BINAP) ₂ (NEt ₃ ) (p-Cl-BINAP is 2,2'-bis (di-p-chlorophenylphosphino) -1 , 1'-meaning binaphthyl) Ru ₂ Cl ₄ (pF-BINAP) ₂ (NEt ₃ ) (pF-BINAP is 2,2'-bis (di-p-fluorophenylphosphino) -1,1'- means _{binaphthyl) Ru 2 Cl 4 (MeBIPH)} 2 (NEt 3) (MeBIPH is 6,6'-dimethyl-2,2'-bis (diphenylphosphino) means 1,1'-biphenyl) Ru ₂ Cl ₄ (BIHNAP) ₂ (NEt ₃ ) (BIHNAP is 2,2'-bis (diphenylphosphino) -5,6,7,
8,5 ', 6', 7 ', 8'-means octahydro-1,1'-binaphthyl) RuHCl (BINAP) ₂ , RuHCl (T-BINAP) ₂ , RuHCl (t-Bu-BINA
P) ₂ , RuHCl (p-MeO-BINAP) ₂ , RuHCl (3,5-DiMe-BINAP) ₂ ,
RuHCl (3,5-Di-t-Bu-BINAP) ₂ , RuHCl (3-Me-BINAP) ₂ , RuH
Cl (p-Cl-BINAP) ₂ , RuHCl (pF-BINAP) ₂ , RuHCl (MeBIP
H) ₂ , RuHCl (BIHNAP) ₂ , [RuCl (benzene) (BINAP)] Cl, [R
uCl (p-cymene) (T-BINAP)] Cl, [RuBr (benzene) (BINAP)]
Br, [RuBr (benzene) (T-BINAP)] Br, [RuBr (p-cymene) (t
-Bu-BINAP)] Br, [RuI (benzene) (BINAP)] I, [RuI (benzene) (T-BINAP)] I, [RuI (benzene) (t-Bu-BINAP)] I, [R
uI (p-simene) (BINAP)] I, [RuI (p-simene) (T-BINAP)] I,
[RuI (p-cymene) (t-Bu-BINAP)] I, [RuI (methyl benzoate)
(BINAP)] I, [RuI (methyl benzoate) (T-BINAP)] I, [RuI
(Methyl benzoate) (t-Bu-BINAP)] I, [RuCl (benzene) (BI
NAP)] ClO ₄ , [RuCl (benzene) (t-Bu-BINAP)] ClO ₄ , [RuCl
(p-Cymene) (BINAP)] PF ₆ , [RuCl (p-Cymene) (BINAP)] B
F ₃ , [RuCl (methyl benzoate) (BINAP)] BPh ₄ , [Ru (acetonitrile) ₄ (BINAP)] (BF ₄ ) ₂ , [RuCl (acetonitrile) ₂ (B
INAP)] Cl, [RuI (p-cymene) (BINAP)] I ₃ , [RuI (p-cymene)
(T-BINAP)] I ₃ , [RuI (p-simene) (t-Bu-BINAP)] I ₃ , Ru (OC
OCH ₃ ) ₂ (BINAP), Ru (OCOCH ₃ ) ₂ (T-BINAP), Ru (OCOCH ₃ ) ₂ (t
-Bu-BINAP), Ru (OCOCF ₃ ) ₂ (BINAP), Ru (OCOCF ₃ ) ₂ (T-BINA
P), Ru (OCOCF ₃ ) ₂ (t-Bu-BINAP).

To carry out the present invention, γ-diketones
(1) as methanol, ethanol, isopropanol, etc.
Of the protic solvent alone or tetrahydrofuran
Or acetone, or their mixed solvent
Or a solvent (preferably a membrane) in which a small amount of water is added to them.
Dissolved in ethanol and ethanol, and the solution was autoclaved.
And put it in ruthenium-optically active phosphine complex
Desired by adding an asymmetric hydrogenation reaction
.Gamma.-hydroxyketones are obtained. In addition, according to the present invention
In the method, the ruthenium compound and BIPHOS were added to the reaction system separately.
In the system, ruthenium-optically active phosphine complex
May be formed. Further, the optical activity used in the present invention
The configuration of the water-soluble phosphine complex to (R) or (S)
By appropriately changing, γ-having a desired configuration
A hydroxyketone can be obtained. The catalyst amount is above
γ-diketones (1) 1/50 to 1/5000 times mol, favorable
More preferably, 1/100 to 1/1000 times mol is added, and hydrogen pressure is 5 to 50 kg /
cm², Preferably 30-50kg / cm ², Reaction temperature 5 ~ 100 ℃,
It is preferably 30 to 50 ° C for 1 to 72 hours, preferably 8 hours
Hydrogenation is carried out by stirring for 20 hours. After the reaction,
Isolate the product by distilling off the solvent and distilling the residue under reduced pressure
Alternatively, treat with silica gel column chromatography.
The target optically active γ-hydroxy
Ketones are obtained with a yield of 50-90%.

[0038]

The present invention will now be described with reference to examples, but the present invention is not limited to these examples. The analytical values in the examples were measured using the following analytical instruments. Gas chromatograph; HITACHI 263-80 Hitachi Ltd. column; Silicon OV-101 Silica capillary φ0.25
mm × 25m (manufactured by GL Sciences Inc.); HEWLETT PACKARD 5890 SERIES II (HHEWLETT PACKARD
Column); Neutrabond 1 silica capillary φ
0.25mm × 25m Measurement temperature; initial temperature 50-150 ℃, heating rate 1-10 ℃ / mi
n High performance liquid chromatograph (hereinafter abbreviated as HPLC); 665-A-
11 (manufactured by Hitachi, Ltd.) Column: COSMOSIL 5SL φ 4.6 mm × 250 mm (manufactured by Nacalai Tesque, Inc.) Developing solvent: hexane / ether = 8 / 1-10 / 1 0.5-1.5 ml
/ min Detector; UV detector 635M (UV-254nm) (manufactured by Hitachi, Ltd.) ¹ H-nuclear magnetic resonance spectrum (hereinafter abbreviated as ¹ H-NMR); AM-40
0 type device (400MHz) (Brooker) Internal standard material; Tetramethylsilane opacity; DIP-4 type device (JASCO Corporation)

Example 1 Synthesis of (-)-5-Hydroxyhexan-2-one To 100 ml of a stainless steel autoclave previously purged with nitrogen, 5 g (0.0438 mol) of 2,5-hexanedione and 10 ml of methanol were added. Ru ₂ Cl ₄ ((R) -T-BINAP) ₂ (NEt ₃ ) 0.
197 g (0.109 mmol) dissolved in 2 ml of methylene chloride and added,
After reacting for 8 hours at a hydrogen pressure of 50 kg / cm ² and a reaction temperature of 50 ° C., the solvent was distilled off, and the residue was purified by silica gel column chromatography using a developing solvent of hexane / ethyl acetate = 5/1. g (-)-5-hydroxyhexan-2-one was obtained. Yield 85.6%. ¹ H-NMR (CDCl ₃ ) δppm; 1.2 (3H, d), 1.68 to 1.76 (2H, m), 2.
1 (3H, s), 2.6 (2H, m), 3.8 (1H, m) [α] _D ²⁵ : −10.09 (C.1.03 ethanol)

The resulting hydroxyketone and (R) -or
An ester was synthesized from (S) -α-methoxy-α-trifluoromethylphenylacetic acid (hereinafter abbreviated as MTPA) and analyzed by HPLC using a developing solvent of hexane / ether = 9/1. It was 100% ee.

Examples 2 to 8 Table 1 shows the results of the operation according to Example 1 except that the catalyst and reaction conditions were changed.

[0042]

[Table 1]

Example 9 Synthesis of (-)-4-hydroxy-1-phenylpentan-1-one Into a 100 ml stainless steel autoclave previously purged with nitrogen, 5 g (0.0284 mol) of 5-phenyl-2,5-pentanedione was added.
And 10 ml of methanol were added, and then [RuI (p-cymene) ((R)
-T-BINAP)] I ₃ 0.2 g (0.142 mmol) was dissolved in 2 ml of methylene chloride and added, and the reaction was carried out at a hydrogen pressure of 50 kg / cm ² and a reaction temperature of 50 ° C. for 40 hours, and the solvent was distilled off. Purification by silica gel column chromatography using a developing solvent of hexane / ethyl acetate = 5/1 gave 4.5 g of (−)-4-hydroxy-1-phenylpentan-1-one. Yield 90.0%. ¹ H-NMR (CDCl ₃ ) δppm; 1.26 (2H, d, J = 6Hz), 1.7 to 1.9 (2H,
m), 3.148, 3.15 (2H, dt, J = 7.08Hz), 3.9 (1H, m), 7.46 (2
H, m), 7.55 (1H, m), 7.98 (2H, m) [α] _D ²⁵ : -14.31 (C.1.02 ethanol)

An ester was synthesized from the obtained γ-hydroxyketone and (R)-or (S) -MTPA, and hexane / ethanol was added.
As a result of analysis using HPLC with a developing solvent of tel = 9/1, the optical purity was 99.6% ee.

Examples 10 to 16 Table 2 shows the results of the operation according to Example 9 except that the catalyst and the reaction conditions were changed.

[0046]

[Table 2]

Example 17 Synthesis of (−)-2-hydroxynonan-5-one 100 ml stainless steel autoclave that had been previously replaced with nitrogen
, 2,5-nonanedione 5 g (0.032 mol) and methanol 10
Add ml and add Ru₂Cl_Four((R) -T-BINAP)₂(NEt ₃) 0.144g
(0.08 mmol) dissolved in 2 ml of methylene chloride and added, hydrogen pressure
50 kg / cm²React at 50 ° C for 20 hours,
After evaporating the solvent, a developing solvent of hexane / ethyl acetate = 4/1
Purified by silica gel column chromatography using
Then, 3.3 g of (−)-2-hydroxynonan-5-one was obtained.
Yield 65.6%.¹ H-NMR (CDCl₃) δppm; 0.9 (3H, t, J = 7.4Hz), 1.2 (3H, d, J =
6.2Hz), 1.3 (2H, m), 1.55 to 1.78 (3H, m), 2.43 (2H, t, J =
7.6Hz), 2.56 (2H, t, J = 7Hz), 3.8 (1H, m) [α]_D ^{twenty five}: -10.19 (C.1.05 ethanol)

Of the obtained alcohol and (R)-or (S)-
The ester was synthesized from MTPA and analyzed by HPLC using a developing solvent of hexane / ether = 95/5. The optical purity was 99.8.
It was% ee.

Example 18 Synthesis of (-)-5-hydroxy-6-phenylhexan-2-one 5 g (0.0261 mol) of 6-phenyl-2,5-hexanedione was placed in a 100 ml stainless steel autoclave which had been previously purged with nitrogen.
Add 10 ml of methanol and methanol, and add [RuI (p-cymene)
((R) -T-BINAP)] I ₃ 0.185 g (0.13 mmol) of methylene chloride 2 m
It is dissolved in 1 l of hydrogen and added at a hydrogen pressure of 50 kg / cm ² at a reaction temperature of 50 ° C.
After reacting for 6 hours and evaporating the solvent, the residue was purified by silica gel column chromatography using a developing solvent of hexane / ethyl acetate = 5/1, and 3.03 g of (−)-5-hydroxy-6-phenyl Hexan-2-one was obtained. Yield 60.2%. ¹ H-NMR (CDCl ₃ ) δppm; 1.72 (1H, m), 1.87 (1H, m), 2.16 (3
H, s), 2.625,2.633 (2H, dt, J = 7Hz), 2.69,2.71 (1H, dd, J =
13.6Hz), 2.811,2.823 (1H, dd, J = 13.6Hz) [α] _D ²⁵ : −3.57 (C.1.05 ethanol)

Of the obtained alcohol and (R)-or (S)-
The ester was synthesized from MTPA, and analyzed by HPLC using a developing solvent of hexane / ether = 8/2, the optical purity was 68.5%.
It was ee.

[0051]

Industrial Applicability The present invention uses a ruthenium-optically active phosphine complex as a catalyst to perform an asymmetric hydrogenation reaction on γ-diketones, thereby producing an intermediate for synthesizing a drug, a biodegradable polymer, It is an excellent method that can efficiently produce optically active γ-hydroxyketones useful in the synthesis of optically active moieties such as fragrances.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI // C07B 53/00 C07B 53/00 B 61/00 300 61/00 300 (72) Inventor Hidenori Unbayashi Nishi, Hiratsuka, Kanagawa Prefecture Hachiman 1-4-11 Takasago International Corporation Fine Chemical Laboratory (56) References JP-A-2-289537 (JP, A) JP-A 1-211551 (JP, A) E. J. Corey et al. Tetrahedron Letters, Vol. 30, No. 46, 1989, p. 6275-6278 Bhabani K .; Sarmah et al. , Tetrahedron, Vol. 47, No. 40, 1991, p. 8587-8600 Hiroyuki Kawano et al. J. Chem. Soc. Chem. Commun, 1988, p. 87-88 M.I. Kitamura et al. J. Am. Chem. Soc. , 1988, Vol. 110, p. 629-631 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07C 49/17 C07C 45/64 C07C 49/24 C07C 49/82 CASREACT (STN)

Claims (6)

(57) [Claims] 1. The following general formula (1): (Wherein R ¹ and R ² represent an alkyl or phenyl group which may have a substituent), and asymmetric hydrogenation is carried out using a ruthenium-optically active phosphine complex as a catalyst. Which is characterized by the following general formula (2): (In the formula, R ¹ and R ² have the same meanings as described above.) A method for producing an optically active γ-hydroxyketone. 2. A ruthenium-optically active phosphine complex is represented by the following general formula (3): embedded image Ru _x H _y Cl _z (BIPHOS) ₂ (S) _p ··· (3) [wherein, BIPHOS Represents a tertiary phosphine represented by the following general formula (a), (b) or (c): ^{R 3, R 4, R 5} , R 6, R 7, R 8, R 9, R 10, R 11, R
¹² , R ¹³ and R ¹⁴ are each a hydrogen atom, a halogen atom,
Represents an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, (S) represents a tertiary amine, and when y is 0, x is 2, z is 4, p is 1, y When is 1, x is 1,
The compound according to claim 1, wherein z is 1 and p is 0]. 3. A ruthenium-optically active phosphine complex is represented by the following general formula (4): [RuA _k (B) _m (BIPHOS)] Y _n ··· (4) (wherein A is Represents a halogen atom, B represents benzene or acetonitrile which may have a substituent, Y represents a halogen atom, ClO ₄ , PF ₆ , BPh ₄ or BF ₄ , and BIP
HOS has the same meaning as described above, and when B is benzene which may have a substituent, k is 1, m is 1, n is 1, and when B is acetonitrile, when k is 1. , M is 1, n is 1, and k is 0, m is 4, and n is 2.). 4. A ruthenium-optically active phosphine complex has the following general formula (5): [RuI (p-cymene) (BIPHOS)] I ₃ (5) (wherein BIPHOS Is a compound represented by the above), and the production method according to claim 1. 5. A ruthenium-optically active phosphine complex is represented by the following general formula (6): embedded image Ru (OCO—R ¹⁵ ) ₂ (BIPHOS) (6) (wherein R ¹⁵ is Represents a hydrogen atom or a lower alkyl group, B
IPHOS has the same meaning as above), and the production method according to claim 1. 6. BIPHOS has the following general formula (a-1): A tertiary phosphine represented by the formula: wherein R ¹⁶ represents a hydrogen atom, a methyl group or a t-butyl group.
Manufacturing method according to any one of items.