JPH0720910B2 - Process for producing optically active carboxylic acid - Google Patents

Description

The present invention relates to a method for producing an optically active carboxylic acid by an asymmetric synthesis method, more specifically, the following general formula (II) (In the formula, R ¹ and R ² each represent a hydrogen atom, an alkyl group, an alkenyl group or an aryl group which may have a substituent, and R ³ has a hydrogen atom, an alkyl group, an alkenyl group or a substituent. And R ¹ , R ² and R ³ are not hydrogen atoms at the same time, and when R ¹ and R ² are hydrogen atoms at the same time, R ³ is not a methyl group and R ^{When 3} is a hydrogen atom, R ¹ and R ² are different groups other than a hydrogen atom.) An α, β-unsaturated carboxylic acid represented by the general formula (II
I) (V) or _{(VII) Ru x H y Cl} z (R 4 -BINAP) 2 (S) p (III) ( wherein, R ⁴ -BINAP formula (IV) Represents a tertiary phosphine represented by, R ⁴ represents a hydrogen atom or a methyl group, S represents a tertiary amine, and when y is 0, x is 2, z is 4, p is 1, and y is 1 Then x is 1,
z is 1 and p is 0. ) (In the formula, XR ⁵ -BINAP is the formula (VI) Represents a tertiary phosphine, R ⁵ represents a hydrogen atom or a lower alkyl group, X represents a hydrogen atom, an amino group, an acetylamino group or a sulfone group, and R ⁶ and R ⁷ represent a lower alkyl group or a halogeno lower group. An alkyl group, a phenyl group which may be substituted by a lower alkyl group, an α-aminoalkyl group or an α-aminophenylalkyl group, or R ⁶ and
R ⁷ together represents an alkylene group, and q is 1 or 2. ) [RuH ₁ (R ⁴ -BINAP) _v ] Y _w (VII) (In the formula, R ⁴ -BINAP has the same meaning as described above, and Y is Cl.
O ₄ , BF ₄ or PF ₆ is shown, and when 1 is 0, v is 1 and w is 2, when 1 is 1, v is 2 and w is 1. General formula (I) characterized by asymmetric hydrogenation as a catalyst (Wherein R ¹ , R ² and R ³ have the same meanings as described above) and relates to a process for producing an optically active carboxylic acid.

[Prior Art] The optically active carboxylic acid represented by the above formula (I) has attracted attention as a raw material for synthesizing various useful compounds, for example, an intermediate for synthesizing a physiologically active substance of a natural product, and a liquid crystal material. It is what

Conventionally, as a method for asymmetrically synthesizing this optically active carboxylic acid, a method using a naturally occurring optically active substance as a raw material,
A method utilizing an asymmetric hydrogenation reaction using a microorganism or a method using an asymmetric hydrogenation using a specific catalyst is known. In particular, as a method for obtaining an optically active carboxylic acid of the formula (I) by asymmetric synthesis from an α, β-unsaturated carboxylic acid represented by the formula (II), a rhodium-optically active phosphine complex is used as a catalyst. A method for performing asymmetric hydrogenation has been reported. That is, in C. Fisher et al .: Tetrahedron Letters, No. 29, (1977) p.2487-2490, asymmetric yield of 27.5% ee was obtained in asymmetric hydrogenation of atropoic acid (2-methylenephenylacetic acid). -I have obtained methylphenylacetic acid. P. Aviron-Violet et al .: J. Mol. Cat., 5 , (197
9), p.41-50, asymmetric hydrogenation of atropaic acid is also described in 7
Asymmetric yield of 0% ee is reported. Also, M. Yamashita
Et al .: Bull. Chem. Soc. Jpn., 55 (1982) p.2917-2921,
Asymmetric hydrogenation of tiglic acid ((E) -2-methyl-2-butenoic acid) gives 2-methylbutyric acid in an asymmetric yield of 62% ee.

[Problems to be solved by the invention]

However, although a method using a natural product as a starting material or a method using a microorganism can obtain a carboxylic acid having a relatively high optical purity, the absolute configuration of the obtained optically active carboxylic acid is limited to a specific one, and a mirror image is obtained. Body synthesis is difficult.
Also, rhodium. Α, β by optically active phosphine catalyst
-The method by asymmetric hydrogenation of an unsaturated carboxylic acid derivative is not sufficient in the optical purity of the obtained carboxylic acid,
Since the production area and production amount of rhodium metal to be used are limited and the price is also expensive, when this is used as a catalyst, the ratio of the price of rhodium in the product price becomes large, There was a drawback that it affected the manufacturing cost of goods.

[Means for solving problems]

In such an actual situation, the present inventor has conducted diligent research to solve the above-mentioned problems, and as a result, if asymmetrical hydrogenation is carried out by using a relatively inexpensive specific ruthenium-optically active phosphine complex as a catalyst, high optical The present invention has been completed by finding that a carboxylic acid having a purity can be obtained.

That is, the present invention relates to an α, β-unsaturated carboxylic acid (II)
Is asymmetric hydrogenation using the ruthenium-optically active phosphine complex represented by the general formula (III), (V) or (VII) as a catalyst to produce an optically active carboxylic acid (I).

To carry out the present invention, an α, β-unsaturated carboxylic acid (I
I) is dissolved in a protective solvent such as methanol, ethanol or methyl cellosolve, and equimolar amounts of teriethylamine, dicyclohexylmethylamine and tri-n- are used depending on the substrate.
Tertiary amines such as butylamine were added and charged into an autoclave, in which ruthenium-optically active phosphine complex was added to the above α, β-unsaturated carboxylic acid at 1/100 to 1/300
Add 0 times mole, hydrogen pressure 4-135kg / cm ² , hydrogenation temperature 0
Hydrogenation is carried out by stirring at -80 ° C for 1 to 100 hours. After the reaction, the solvent is distilled off and the residue is distilled under reduced pressure to obtain the desired optically active carboxylic acid (I) in a substantially quantitative yield.

Α, β-unsaturated carboxylic acid (II) which is a raw material of the present invention
, R ¹ and R ² are each hydrogen atom in the above-mentioned formula (II), an alkyl group, an aryl group which may have an alkenyl group or a substituent, R ³ is a hydrogen atom, an alkyl group, an alkenyl group, or A naphthyl group which may have a substituent, R ¹ and R ²
And R ³ is not a hydrogen atom at the same time, if R ¹ and R ² are not hydrogen atoms at the same time not R ³ is a methyl group, when R ³ is a hydrogen atom R ¹ and R ² hydrogen It is necessary that they are different groups other than atoms. This is a condition that the carbon atom at the α-position or β-position of the target carboxylic acid (I) obtained by the present invention becomes an asymmetric hydrogen atom and has optical activity. As an example of this α, β-unsaturated carboxylic acid (II),
Tiglic acid, angelic acid ((Z) -2-methyl-2-butenoic acid), 2-methyl-2-pentenoic acid, 2-methylenenonanoic acid, 2-methylcinnamic acid, 3-methylcinnamic acid, 2-phenyl Examples include cinnamic acid, gellan acid, and 6-methoxy-α-methylene-2-naphthalene acetic acid.

In the present invention, the ruthenium-optically active phosphine complex (III) used as a catalyst is prepared by T. Ikariya et al .; J. Chem. So.
c., Chem. Commun., (1985) p.922-924 and JP-A-61-636.
It can be obtained by the method disclosed in No. 90. That is, the complex of the formula (III) when y = 0 is ruthenium chloride and cycloocta-1,5-diene (hereinafter, COD
Abbreviated) in an ethanol solution and [RuCl ₂ (COD)] _n 1 mol and 2,2′-bis (di-pR ⁴ -phenylphosphino) -1,1′-binaphthyl (R ⁴
-BINAP) (1.2 mol) can be obtained by reacting by heating in a solvent such as toluene or ethanol in the presence of 4 mol of a tertiary amine such as triethylamine. When y = 1, the compound is [RuCl ₂ (COD)] _n 1 mol, R ⁴ -BINAP2.25
Obtained by reacting moles with 4.5 moles of a tertiary amine.

By using optically active R ⁴ -BINAP in the above production method, a ruthenium-phosphine complex (III) having optically active properties corresponding thereto can be obtained.

Examples of the above ruthenium-optically active phosphine complex (III) include the following.

Ru ₂ Cl ₄ (BINAP) ₂ (NEt ₃ ) [BINAP is 2,2'-bis (diphenylphosphino) -1,
Bu ₂ Cl ₄ (T-BINAP) ₂ (NEt ₃ ) [T-BINAP means 2,2′-bis (di-P-tolylphosphino) -1,1′-binaphthyl] RuHCl (BINAP) ₂ RuHCl (T-BINAP) ₂ optically active phosphine complex (V) is prepared, for example, according to the method of Japanese Patent Application No. 61-108888 filed by the present inventors.
Ru ₂ HCl ₄ (XR ⁵ -BINAP) ₂ (NEt ₃ ) obtained by the above method is used as a raw material, and this and a carboxylic acid salt are heated in an alcohol solvent such as methanol, ethanol or t-butanol at about 20 to 110 ° C. 3 to 15 at temperature
After reacting for a time, 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 from ethyl acetate or the like.

Further, the complex having a trifluoroacetate group is a diacetate complex Ru (XR ⁵ -BINAP) (O ₂ CC
H ₃ ) ₂ with trifluoroacetic acid in methylene chloride as solvent
It can be obtained by reacting at 25 ° C for about 12 hours.

Further, in the case of producing a complex in which 2 equivalents of a ligand are coordinated to ruthenium metal, that is, q is 2, RuHCl (XR ⁵ -BINAP) ₂ obtained by the above method is used as a raw material and a carbohydrate. The acid salt may be reacted in a solvent such as methylene chloride.

By using optically active XR ⁵ -BINAP in the above production method, a ruthenium-phosphine complex (V) having optically active properties corresponding to this is used.
Can be obtained. The following are mentioned as an example of such a complex.

_{Ru (BINAP) (O 2 CCH} 3) 2 Ru (BINAP) (O 2 CCF 3) 2 Ru (T-BINAP) (O 2 CCF 3) 2 Ru (T-BINAP) 2 (O 2 CCH 3) 2 Ru (BINAP) (O ₂ Ct-Bu) ₂ Ru (BINAP) (O ₂ CPh) ₂ Ru (T-BINAP) (O ₂ CCH ₃ ) ₂ Ru (t-BuBINAP) (O ₂ CCH ₃ ) ₂ Ru (Amino BINAP) (O ₂ CCH ₃ ) ₂ Ru (Acetylamino BINAP) (O ₂ CCH ₃ ) ₂ Ru (Sulfonated BINAP) (O ₂ CCH ₃ ) _Two Ru (T-BINAP) ₂ (O ₂ CCF ₃ ) ₂ The symbols in the above formula are explained as follows. t-Bu: tert-butyl group, i-Pr: isopropyl group, Ph: phenyl group, t-BuBINAP: 2,2'-bis (di-p-tert-butylphenylphosphino) -1,1'- Binaphthyl, sulfonated BINAP: 2,2'-bis (diphenylphosphino) -5,
5'-bis (sodium sulfonate) -1,1'-binaphthyl,
Amino BINAP: 2,2'-bis (diphenylphosphino)-
5,5'-bis (amino) -1,1'-binaphthyl, acetylamino BINAP: 2,2'-bis (diphenylphosphino)-
5,5'-Bis (acetylamino) -1,1'-binaphthyl The optically active phosphine complex (VII) can be obtained by the method filed by the present inventors as Japanese Patent Application No. 61-184651. That is, in the complex of the formula (VII), l is 0,
The complex in the case where v is 1 and w is 2 uses Ru ₂ Cl ₄ (R ⁴ -BINAP) ₂ (NEt ₃ ) obtained by the above-mentioned method as a raw material, and uses this compound and the following formula (VIII) MY (VIII (In the formula, M represents a metal such as Na, K, Li, Mg, and Ag, and Y represents Cl.
O ₄ , BF ₄ , and PF ₆ ) and a salt represented by the following formula (IX) R ⁸ R ⁹ R ¹⁰ R ¹¹ AB (IX) (wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ mean an alkyl group having 1 to 16 carbon atoms, a phenyl group and a benzyl group, A means a nitrogen atom or a phosphorus atom, and B means a halogen atom). The indicated quaternary ammonium salt or quaternary phosphonium salt is used as a phase transfer catalyst and reacted to give a ruthenium-phosphine complex. Ru ₂ Cl ₄ (R-BINAP) ₂ (N
The reaction between Et ₃ ) and the salt (VIII) is carried out by adding both and a phase transfer catalyst (IX) in a mixed solvent of water and methylene chloride and stirring. The amounts of the salt (VIII) and the phase transfer catalyst (IX) are 2 to 10 times mol (preferably 5 times mol) and 1/100 to 1/10 times mol of ruthenium, respectively. Reaction is 5
Stirring at a temperature of -30 ° C for 6-18 hours, usually 12 hours is sufficient. As salts, Na, K, Li, Mg, Ag perchlorate,
Borofluoride and hexafluorophosphate are used. The phase transfer catalyst (IX) is described in the literature [eg, WP
Weber, GW Gokel co-authored, Iwao Tabushi, Takako Nishitani, "Phase Transfer Catalyst" Kagaku Dojin Co., Ltd. (1978-9-5, 1st edition) are used. After completion of the reaction, the reaction product is allowed to stand still, liquid separation operation is performed, the aqueous layer is removed, the methylene chloride solution is washed with water, and then methylene chloride is distilled off under reduced pressure to obtain the desired product.

Alternatively, Ru (R ⁴ -BINAP) (O ₂ CC
H ₃ ) ₂ as a raw material, and an acid represented by the following formula (X) HY (X) (wherein Y represents ClO ₄ , BF ₄ , and PF ₆ ) in a mixed solvent of methylene chloride and methanol. Stir at to react. The amount of the acid (X) is 2 to 6 times mol, preferably 4 times mol, of ruthenium.
For the reaction, stirring at a temperature of 5 to 30 ° C. for 6 to 18 hours, usually 12 hours is sufficient.

When a complex of the formula (VII) in which 1 is 1, v is 2, and w is 1 is prepared, RuHCl (R
^4- BINAP) ₂ as a raw material may be reacted with salt (VIII) in a mixed solvent of methylene chloride and water in the presence of a phase transfer catalyst (IX). The amounts of the salt (VIII) and the phase transfer catalyst (IX) are 2 to 10 times mol (preferably 5 times mol) and 1 to 100 to 1/10 times mol of ruthenium, respectively. For the reaction, stirring at a temperature of 5 to 30 ° C. for 6 to 18 hours, usually 12 hours is sufficient.

Examples of the complex represented by the formula (VII) are as follows.

〔Example〕

 Next, the present invention will be described with reference to examples and examples.

The analysis in the examples was carried out using the following analytical instruments.

Gas chromatograph: Shimadzu GC-9A (manufactured by Shimadzu Corporation) Column: OV-101 silica capillary, φ 0.25 mm x 25 m (manufactured by Gascro Industrial Co., Ltd.) Measurement temperature 100-250 ° C at 3 ° C / min Temperature rising high performance liquid chromatograph E: Hitachi Liquid Chromatograph E 665A-11 (manufactured by Hitachi, Ltd.) Column: Chemeopack Nucleosil 100-3, φ 4.6 mm x 300 mm (manufactured by Chemco) Developing solvent: Hexane: Ether = 7 : 3 1 ml / min Detector: UV detector 635M (UV-254) (manufactured by Hitachi, Ltd.) ¹ H Nuclear magnetic resonance spectrum: JNM-GX400 type (400 MHz) (manufactured by JEOL Ltd.) Internal standard: Tetra Methylsilicon polarimeter: polarimeter DIP-4 (manufactured by JASCO Corporation) ³¹ P nuclear magnetic resonance spectrum (hereinafter abbreviated as ³¹ PNMR): measured using JNM-GX400 type (161 MHz), chemical shift 85% phosphoric acid
Measured as an external standard Reference example 1 Ru ₂ Cl ₄ ((−)-T-BINAP) ₂ (NEt ₃ ) (di [2,2′-bis (di-p-tolylphosphino) -1,1′-binaphthyl]
Tetrachlorozirthenium triethylamine) synthesis: [RuCl ₂ (COD)] n 1 g (3.6 mmol) and (−)-T-BINA
P2.9 g (4.3 mmol) was placed in a 250 ml Schlenk tube, and after nitrogen substitution was sufficiently performed, triethylamine 1.5
g and 50 ml of toluene were added, and the mixture was heated under reflux for 6 hours for reaction. After completion of the reaction, the solvent was distilled off under reduced pressure. The crystals were dissolved in methylene chloride, passed over Celite, and the solution was concentrated to dryness to give a dark red solid Ru ₂ Cl ₄ ((−)-T-BINAP) ₂
(NEt ₃ ) 3.6g was obtained. Yield 100%.

Elemental analysis value: C ₁₀₂ H ₉₅ Cl ₄ NP ₄ Ru ₂ as Ru CHP theoretical value (%): 11.21 67.96 5.31 6.87 actual measurement value (%): 10.97 67.51 5.88 6.46 ³¹ P NMR (CDCl ₃ ) δppm: 49.65 (s) 49.89 (s) 51.07 (s) 51.30 (s) Reference Example 2 RuHCl ((+)-BINAP) ₂ (di [2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] hydridochloridorthenium ): [RuCl ₂ (COD)] n 0.5 g (1.8 mmol), (+)-BINA
P2.6 g (4.1 mmol) was put into a 250 ml Schlenk tube, and after nitrogen substitution was sufficiently performed, triethylamine 0.8 g was added.
(8 mmol) and 50 ml of ethanol were placed in a reactor, and 6
The mixture was heated under reflux for reaction. After the reaction was completed, ethanol was distilled off under reduced pressure and dried to give yellow crystals of RuHCl.
(2.8 g) of ((+)-BINAP) ₂ was obtained. Yield 100%.

Elemental analysis value: C ₈₈ H ₆₅ ClP ₄ Ru Ru CHP theoretical value (%): 7.31 76.43 4.74 8.96 Actual value (%): 6.95 76.17 5.15 8.67 ³¹ P NMR (CDCl ₃ ) δppm: 21.90 (t, J = 0.83) Hz) 37.74 (t, J = 0.83Hz) Reference Example 3 Ru ((−)-BINAP) (O ₂ CCH ₃ ) ₂ ([2,2′-bis (diphenylphosphino) -1,1′-binaphthyl ] Synthesis of Ruthenium-Diacetate: Ru ₂ Cl ₄ ((−)-BINAP) ₂ (NEt ₃ ) 1.43 g synthesized from (−)-BINAP according to the method shown in Reference Example 1
(0.9 mmol) and 3.06 g (37 mmol) of sodium acetate,
The mixture was placed in a 250 ml Schlenk tube, and after sufficiently purging with nitrogen, 100 ml of t-butanol was added, and the mixture was heated under reflux for 12 hours for reaction. After completion of the reaction, t-butanol was distilled off under reduced pressure of 20 mmHg to dryness, followed by extraction twice with 10 ml of ethyl ether. The ethyl ether was evaporated to dryness, and the resulting solid was further extracted twice with 10 ml of ethanol. The extract was concentrated to dryness and the crude Ru ((−)-BINAP) (O ₂ CCH ₃ ) ₂ 1.
Got 5g. This product was recrystallized from ethyl acetate to obtain 0.79 g of a yellowish brown solid. Yield 52%.

Melting point: 180-181 ℃ (decomposition).

Elemental analysis value: C ₄₈ H ₃₈ O ₄ P ₂ Ru Ru PCH theoretical value (%): 12.01 7.36 68.48 4.55 Actual value (%): 11.85 7.28 68.35 4.61 ³¹ P NMR (CDCl ₃ ) δppm: 65.00 (s) ¹ 1 H NMR (CDCl ₃ ) δ ppm: 6.5 to 7.8 (m, 32H, naphthyl ring and phenyl proton) Reference Example 4 Ru ((−)-T-BINAP) (O ₂ CCF ₃ ) ₂ (2,2′-bis (di-p-tolylphosphino)- Synthesis of (1,1′-binaphthyl] ruthenium-ditrifluoroacetate): Ru ((−)-T-BINAP) (O) synthesized from (−)-T-BINAP according to the method shown in Reference Example 3. ₂ CCH ₃ ) ₂ 0.74
g (0.82 mmol) was preliminarily nitrogen-substituted 250
Put it in a 10 ml Schlenk tube, dissolve in 10 ml of methylene chloride,
A homogeneous solution was prepared. 0.14 ml of trifluoroacetic acid (1.81
Was added and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and a brown solid Ru ((−)-T-BI
NAP) (O ₂ CCF ₃ ) ₂ 0.7 g was obtained. Yield 91%.

Elemental analysis value: C ₅₂ H ₄₀ F ₆ O ₄ P ₂ Ru as Ru C HP theoretical value (%): 10.05 62.09 4.01 6.16 measured value (%): 9.89 62.27 4.15 5.82 ³¹ P NMR (CDCl ₃ ) δppm: 59.91 (S) of Reference Example 5 Ru ((−)-BINAP)] (BF ₄ ) ₂ ([2,2′-bis (diphenylphosphino) -1,1′-binaphthyl] ruthenium-ditetrafluoroborate) Synthesis: Ru ((−)-BINAP) (O ₂ CCH ₃ ) ₂₀ obtained in Reference Example 3 above.
Put 51 g (0.61 mmol) in a Schlenk tube and replace with nitrogen sufficiently, then methylene chloride 7 ml, methanol 7 ml,
0.52 ml (2.48 mmol) of 42% hydrofluoric acid aqueous solution was added, and the mixture was stirred at room temperature for 12 hours. Then concentrate under reduced pressure,
0.53 g of a tan solid [Ru ((−)-BINAP)] (BF ₄ ) ₂ was obtained. Yield 97.2%.

Elemental analysis value: C ₄₄ H ₃₂ B ₂ F ₈ P ₂ Ru as Ru PCH theoretical value (%): 11.26 6.90 58.90 3.59 measured value (%): 10.88 6.51 58.62 3.82 ³¹ P NMR (CDCl ₃ ) δppm: 10.357 (d , J = 48.9Hz) 77.450 (d, J = 48.9Hz) Reference Example 6 [Ru ((+)-T-BINAP)] (ClO ₄ ) ₂ ([2,2′-bis (di-p-tolylphosphino)) Synthesis of -1,1, '-binaphthyl] ruthenium perchlorate): 0.54 g of Ru ₂ Cl ₄ ((+)-T-BINAP) ₂ (NEt ₃ ) obtained by the method shown in Reference Example 1 above. 0.3 mmol) into a 250 ml Schlenk tube, and after sufficiently purging with nitrogen, 60 ml of methylene chloride was added, and then 0.36 g (3.0 mmol) of sodium perchlorate was dissolved in 60 ml of water and triethylbenzyl. Ammonium bromide 16
After adding mg (0.06 mmol) dissolved in 3 ml of water, the mixture was reacted at room temperature for 12 hours with stirring. After the reaction,
Allow to stand, perform liquid separation operation to remove water layer, distill off methylene chloride under reduced pressure, and dry under reduced pressure to obtain dark brown solid [Ru ((+)-T-BINAP)] (ClO ₄ ) ₂ 0.59 g was obtained.
Yield 99.6%.

Elemental analysis value: C ₄₈ H ₄₀ Cl ₂ O ₈ P ₂ Ru Ru PCH theoretical value (%): 10.32 6.33 58.90 4.12 Actual value (%): 10.08 5.97 58.61 4.53 ₃₁ P NMR (CDCl ₃ ) δppm: 12.920 (d , J = 41.1Hz) 61.402 (d, J = 41.1Hz) Example 1 Production of (2S)-(+)-2-methylbutyric acid: (E) -2-methyl-in a 100 ml stainless steel autoclave preliminarily replaced with argon. 2-Butenoic acid (0.2 g, 2 mmol) and methanol (20 ml) were added, followed by Ru [(-)-BINAP)] (BF ₄ ) ₂ 6.0 mg (0.007 mmol) synthesized in Reference Example 5, and hydrogen pressure was 4 kg. Hydrogenation was carried out for 12 hours at a reaction temperature of 20 ° C./cm ² , and the solvent was distilled off to obtain 0.2 g of 2-methylbutyric acid. Yield 100%. ¹ HNMR (CDCI ₃ ) δppm: 0.95 (t, 3H), 1.17 (d, 3H), 1.15 to 2.00 (m, 2H), 2.4 (m, 1H), 9.76 (s, 1H) Optical rotation: ▲ [α ] ²⁵ _D ▼ + 18.05 ° (neat) The result of high performance liquid chromatography analysis was conducted by synthesizing amide from the obtained carboxylic acid and (R)-(+)-1- (1-naphthyl) ethylamine. , The original carboxylic acid is (2S)-(+)-2-methylbutyric acid 95.8% and (2R)-(-)
-2-Methylbutyric acid 4.2% mixture (2S)-(+)-2
-The optical purity of methylbutyric acid was 91.6% ee.

Example 2 Preparation of (2R)-(-)-2-Methylbutyric Acid: 0.2 g (2 mmol) of (E) -2-methyl-2-butenoic acid and 0.39 of dicyclohexylmethylamine were placed in a 100 ml stainless steel autoclave previously purged with argon. g (2 mmol), tetrahydrofuran (2 ml) and ethanol (20 ml) were added, and then Ru ₂ Cl ₄ ((+)-BINAP) ₂ (NEt ₃ ) 6.3 was synthesized in the same manner as in Reference Example 1 using (+)-BINAP as a raw material.
mg (0.004 mmol) was added, hydrogenation was carried out at a hydrogen pressure of 4 kg / cm ² and a reaction temperature of 0 ° C. for 12 hours, and the solvent was distilled off to obtain 0.2 g of 2-methylbutyric acid. Yield 100%.

Optical rotation: ▲ [α] ²⁵ _D ▼ -17.30 ° (neat) The amide was synthesized by the same method as in Example 1 and analyzed. As a result, the optical purity of 2-methylbutyric acid was 86.9% ee.

Example 3 Production of (2R)-(−)-2-Methylbutyric Acid: In a 100 ml stainless steel autoclave purged with argon, 0.2 g (2 mmol) of (E) -2-methyl-2-butenoic acid was added.
And 0.2 g (2 mmol) of triethylamine, 2 ml of tetrahydrofuran and 20 ml of ethanol were added, and subsequently 6.9 mg (0.005 mmol) of RuHCl ((+)-BINAP) ₂ synthesized in Reference Example 2 was added, and hydrogen pressure was 30 kg / cm ² , Hydrogenation was carried out at a reaction temperature of 80 ° C. for 14 hours, and the solvent was distilled off to obtain 0.2 g of 2-methylbutyric acid. Yield 100%.

Optical rotation: ▲ [α] ²⁵ _D ▼ + 15.60 ° (neat) The amide was synthesized by the same method as in Example 1 and analyzed. As a result, the optical purity of 2-methylbutyric acid was 77.0% ee.

Example 4 Preparation of (2S)-(+)-2-methylbutyric acid: (Z) -2-in a 100 ml autoclave purged with argon.
Methyl-butenoic acid 0.2 g (2 mmol) and methanol 20 m
l, dicyclohexylmethylamine 0.39 g (2 mmol)
Was added and dissolved, and according to the method shown in Reference Example 3, (+)-
Ru ((+)-BINAP) (O ₂ CC
H ₃ ) ₂ 3.4 mg (0.004 mmol) was added, and the hydrogen pressure was 125 kg / cm ²
Hydrogenation was carried out by stirring at 25 ° C. for 4 hours, and the solvent was distilled off to obtain 0.2 g of 2-methylbutyric acid. Yield 100%.

Optical rotation: ▲ [α] ²⁵ _D ▼ -12.25 ° (neat) The amide was synthesized in the same manner as in Example 1 and analyzed. As a result, the optical purity of (2S)-(+)-2-methylbutyric acid was determined. Is 57.9
It was% ee.

Example 5 Preparation of 2-methylvaleric acid: (E) -2-into a 100 ml autoclave purged with argon.
0.23 g (2 mmol) of methyl-2-pentenoic acid and 20 ml of methanol were added, and Ru ((-)-synthesized in Reference Example 3 was added thereto.
BINAP) (O ₂ CCH ₃ ) ₂ 8.4 mg (0.01 mmol) was added, and hydrogenation was carried out at a hydrogen pressure of 4 kg / cm ² at a reaction temperature of 25 ° C. for 24 hours,
The solvent was distilled off to obtain 0.23 g of 2-methylvaleric acid. Yield 1
00%.

Boiling point: 50 ° C / 0.07 mmHg ¹ H NMR (CDCl ₃ ) δppm: 0.92 (t, 3H), 1.18 (d, 3H), 1.3 to 1.5 (m, 2H),
1.6 to 1.75 (m, 1H), 2.48 (m, 1H), 11.00 (s, 1H) Optical rotation: ▲ [α] ²⁵ _D ▼ + 1.40 ° (neat) Synthesized amide by the same method as in Example 1. As a result of the analysis, the optical purity of 2-methylvaleric acid was 77.9% ee.

Example 6 Production of (2R)-(−)-2-methylnonanoic acid: To an argon-substituted 200 ml autoclave, 3.0 g (17.6 mmol) of 2-methylenenonanoic acid and 50 ml of ethanol were added, and this was shown in Reference Example 6. Follow the method (-)-T-BI
Synthesized using NAP as a raw material [Ru ((−)-T-BINAP)]
(ClO ₄ ) ₂ 6.9 mg (0.007 mmol) was added, and the hydrogen pressure was 30 kg /
Hydrogenation was carried out for 15 hours at a reaction temperature of 20 ° C. in cm ² , and the solvent was distilled off to obtain 3.0 g of 2-methylnonanoic acid. Yield 100
%.

Boiling point: 110-112 ° C / 2mmHg ¹ H NMR (CDCl ₃ ) δppm: 0.85-1.80 (m, 18H), 2.24-2.75 (m, 1H), 11.90 (s, 1H) Optical rotation: ▲ [α] ²⁵ _D ▼ -5.40 ° (c2.11, ethanol) The amide was synthesized in the same manner as in Example 1 and analyzed. As a result, the optical purity of (2R)-(−)-2-methylnonanoic acid was found to be
It was 37% ee.

Example 7 Preparation of (3S)-(−)-Citronellic Acid: In a 100 ml autoclave purged with argon, gellan acid was added.
Ru ((+)-BINAP synthesized by adding 0.34 g (2 mmol), 20 ml of methanol and 0.39 g (2 mmol) of dicyclohexylmethylamine according to the method described in Reference Example 3 using (+)-BINAP as a raw material. ) (O ₂ CCH ₃ ) ₂ 5.6 mg (0.007
Mmol) was added and the reaction was carried out for 12 hours at a hydrogen pressure of 100 kg / cm ² and a reaction temperature of 25 ° C., and the solvent was distilled off to obtain 0.34 g of citronellic acid. Yield 100%.

Boiling point: 100 ° C to 0.07 mmHg ¹ H NMR (CDCl ₃ ) δppm: 0.97 (d, 3H), 1.1 to 1.5 (m, 2H), 1.60 (s, 3H), 1.67 (s, 3H), 1.73 to 2.50 (M, 4H), 5.08 (t, 1H), 12.30 (s, 1H) Optical rotation: ▲ [α] ²⁵ _D ▼ -7.82 ° (c2.99, methanol) An amide was synthesized in the same manner as in Example 1. As a result of analysis, the optical purity of (3S)-(-)-citronellic acid was 8
It was 7.0% ee.

Example 8 Preparation of naproxen (6-methoxy-α-methyl-2-naphthalene acetic acid): 0.45 g (2 mmol) 6-methoxy-α-methylene-2-naphthalene acetic acid and 20 ml methanol in a 100 ml autoclave purged with argon. , Dicyclohexylmethylamine
0.39 g (2 mmol) was added, and Ru ((−)-TB synthesized according to Reference Example 3 using (−)-T-BINAP as a raw material was added.
INAP) (O ₂ CCH ₃ ) ₂ 9.0 mg (0.010 mmol) was charged, hydrogen pressure was 135 kg / cm ² , hydrogenation was carried out for 12 hours at a reaction temperature of 17 ° C., and the solvent was distilled off to give 0.39 g of naproxen. Obtained. Yield 84%.

Melting point: 154-155 ° C ¹ H NMR (CDCl ₃ ) δppm: 1.57 (d, 3H), 3.86 (q, 1H), 3.90 (s, 3H), 7.07 to 7.87 (m, 6H), 10.83 (s, 1H) Optical rotation: ▲ [α] ²⁵ _D ▼ + 59.21 ° (c1.08, chloroform) The amide was synthesized in the same manner as in Example 1 and analyzed. As a result, the optical purity of naproxen was 90.4% ee. It was.

Example 9 Preparation of Naproxen: To an autoclave of 100 ml purged with argon, 0.45 g (2 mmol) of 6-methoxy-α-methylene-2-naphthalene acetic acid and 20 ml of methanol were added, and Ru ₂ Cl synthesized in Reference Example 1 was added thereto. ₄ ((-)-T-BINAP) ₂ (NEt ₃ ) 3.6 mg (0.00
(4 mmol) was added, hydrogenation was carried out at a hydrogen pressure of 40 kg / cm ² at a reaction temperature of 20 ° C. for 24 hours, and the solvent was distilled off to obtain 0.42 g of naproxen. Yield 92%.

Melting point: 154-155 ° C ¹ H NMR (CDCl ₃ ) δppm: 1.57 (d, 3H), 3.86 (q, 1H), 3.90 (s, 3H), 7.07 to 7.87 (m, 6H), 10.83 (s, 1H) Optical rotation: ▲ [α] ²⁵ _D ▼ + 49.0 ° (c1.01, chloroform) An amide was synthesized in the same manner as in Example 1 and analyzed. As a result, the optical purity of naproxen was 74% ee. It was.

Example 10 Production of naproxen: To a 100 ml autoclave substituted with argon, 0.45 g (2 mmol) of 6-methoxy-α-methylene-2-naphthaleneacetic acid and 20 ml of methanol were added, and Ru (( -)-T-BINAP) (O ₂ CCF ₃ ) ₂ 2.0 mg (0.002 mmol) was added, hydrogenation was carried out at a hydrogen pressure of 40 kg / cm ² and a reaction temperature of 20 ° C. for 24 hours, and the solvent was distilled off, 0.43 g of naproxen was obtained. Yield 93.7%.

Melting point: 154-155 ° C ¹ H NMR (CDCl ₃ ) δppm: 1.57 (d, 3H), 3.86 (q, 1H), 3.90 (s, 3H), 7.07 to 7.87 (m, 6H), 10.83 (s, 1H) Optical rotation: ▲ [α] ²⁵ _D ▼ + 38.87 ° (c0.98, chloroform) The amide was synthesized in the same manner as in Example 1 and analyzed. As a result, the optical purity of naproxen was 58.8% ee. It was.

Example 11 Preparation of (3S)-(+)-3-phenylbutyric acid: (Z) -3-in a 100 ml autoclave purged with argon.
0.32 g (2 mmol) of methylcinnamic acid and 20 ml of methanol were added, and Ru ((+)-BINAP) (O ₂ CCH ₃ ) ₂ 2.9 mg was synthesized according to Reference Example 3 using (+)-BINAP as a raw material.
(0.0034 mmol), and hydrogen pressure 104kg / cm ² , 7 at 25 ℃
Reaction was carried out for 0 hours, the solvent was distilled off, and 0.32 g of (3S)-
(+)-3-Phenylbutyric acid was obtained. Yield 100%.

Boiling point: 170 ° C to 0.05 mmHg ¹ H NMR (CDCl ₃ ) δppm: 1.30 (d, 3H), 2.57 (d, 1H), 2.60 (d, 1H), 3.27 (m, 1H), 7.32 (broads, 5H ), 12.20 (s, 1H) Optical rotation: ▲ [α] ²⁵ _D ▼ + 0.44 ° (c0.94, benzene) The amide was synthesized in the same manner as in Example 1 and the result of the analysis was (3S The optical purity of)-(+)-phenylbutyric acid is 84.8
It was% ee.

〔The invention's effect〕

The present invention uses a ruthenium-optically active phosphine complex as a catalyst to asymmetrically hydrogenate an α, β-unsaturated carboxylic acid to obtain various useful raw materials for the synthesis of compounds, such as natural bioactive substances. It is possible to industrially advantageously produce an optically active carboxylic acid which can be widely used as an intermediate for synthesis and a liquid crystal material.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // B01J 31/24 C07B 53/00 B 7419-4H 61/00 300 (72) Inventor Susumu Akutagawa 1080-22, Shinohara-cho, Kohoku-ku, Yokohama-shi, Kanagawa (56) References JP 62-185044 (JP, A) JP 63-152337 (JP, A)

Claims (1)

[Claims] 1. The following general formula (II): (In the formula, R ¹ and R ² each represent a hydrogen atom, an alkyl group, an alkenyl group or an aryl group which may have a substituent, and R ³ has a hydrogen atom, an alkyl group, an alkenyl group or a substituent. And R ¹ , R ² and R ³ are not hydrogen atoms at the same time, and when R ¹ and R ² are hydrogen atoms at the same time, R ³ is not a methyl group and R ^{When 3} is a hydrogen atom, R ¹ and R ² are different groups other than a hydrogen atom.) The α, β-unsaturated carboxylic acid represented by the following general formula (III), (V) or ( _{VII) Ru x H y Cl z} (R 4 -BINAP) 2 (S) p (III) ( wherein, R ⁴ -BINAP formula (IV) Represents a tertiary phosphine, R ⁴ represents a hydrogen atom or a methyl group, S represents a tertiary amine, and when y is 0, x is 2, z is 4, p is 1, and y is 1. Then x is 1,
z is 1 and p is 0. ) (In the formula, XR ⁵ -BINAP is the formula (VI) Represents a tertiary phosphine represented by, R ⁵ represents a hydrogen atom or a lower alkyl group, X represents a hydrogen atom, an amino group, an acetylamino group or a sulfone group, and R ⁶ and R ⁷ represent a lower alkyl group, a halogeno lower group. An alkyl group, a phenyl group which may be substituted by a lower alkyl group, an α-aminoalkyl group or an α-aminophenylalkyl group, or R ⁶ and
R ⁷ together represents an alkylene group, and q is 1 or 2. ) [RuH ₁ (R ⁴ -BINAP) _v ] Y _w (VII) (In the formula, R ⁴ -BINAP has the same meaning as described above, and Y is Cl.
O ₄ , BF ₄ or PF ₆ is shown, and when 1 is 0, v is 1, w is 2, and when 1 is 1, v is 2 and w is 1. General formula (I) characterized by asymmetric hydrogenation as a catalyst (Wherein R ¹ , R ² and R ³ have the same meanings as described above), and a process for producing an optically active carboxylic acid.