JP3493206B2 - Process for producing optically active β-amino acids - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing optically active β-amino acids by asymmetric hydrogenation.
Asymmetric hydrogenation of -N-acylamino-3-substituted alkyl- (Z) -acrylic acid using a specific catalyst to produce an optically active 3-N-acylamino-3-substituted alkylpropionic acid, and further deacylation And a method for producing an optically active β-amino acid.

Optically active β-amino acids are extremely useful compounds as raw materials for synthesizing various useful compounds, for example, intermediates for synthesizing physiologically active peptides, and important intermediates for β-lactam antibiotics. Is.

[0003]

2. Description of the Related Art Conventionally, the problems to be solved by the invention
As a method for asymmetrically synthesizing optically active amino acids, (1)
Diastereoselective asymmetric synthesis from compounds with chiral auxiliary, (2) Conversion of optically active α-amino acid to β-amino acid, (3) Prochiral reaction using a specific catalyst A method for asymmetrically hydrogenating 3-aminoacrylic acids is known.

However, the methods (1) and (2) require an equivalent chiral auxiliary or an optically active α-amino acid, and therefore β-scale on a large scale.
There are major restrictions when performing amino acid synthesis.
As a method for asymmetric hydrogenation of prochiral 3-aminoacrylic acids of (3), a method for asymmetric hydrogenation using a rhodium-optically active phosphine complex catalyst has been reported [Tetrahedron Let
, 1978, 1119.], but the obtained asymmetric yield (2.6 to 78% ee) is not satisfactory. On the other hand, for the asymmetric hydrogenation reaction catalyzed by ruthenium complex, see (E)
3-acetamido-2-butenoic acid methyl ester with an optical purity of 96% ee as a substrate a 3-Asetoami bleed Tan acid methyl ester, also (E) -3-acetamido-5-methyl-2-hexenoic acid methyl ester, (E) -3-acetamido-3- each phenyl-2-propenoic acid methyl ester 3-acetamido-5-methylcarbamoyl Ruhe hexa <br/> phosphate ester, 3-acetamido-3-phenyl-
Reported to give the flop propane acid methyl ester with an optical purity of 90% ee [TetrahedronAsymmetry, 1991,2, 543-554.]
However, in this report, only when the substrate olefinic acid ester has the configuration of the (E) form, a hydrogenation product with high optical purity is obtained, whereas the configuration of the (Z) form is provided. It has been reported that when the geometric isomer is used as a substrate, the hydrogenation product is only given in a low optical yield of up to 9% ee.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the inventors of the present invention have found that 3-N-acylamino compounds using a relatively inexpensive optically active ruthenium-phosphine complex as a catalyst. -3-substituted alkyl- (Z)-
If asymmetric hydrogenation of acrylic acids is performed, β with high optical purity
-The present invention has been completed by finding that amino acids can be obtained. That is, the present invention has the general formula (I)

[0006]

[Chemical 7]

(In the formula, R ¹ represents a lower alkyl group, a phenyl group or a benzyloxy group. R ² represents a lower alkyl group, the hydrogen atom of which may be substituted with a phenyl group or an alkoxycarbonyl group. ) (Z) -3-
The N- acylamino-3-substituted alkylene luer acrylic acids,
The general formula (II) is characterized in that asymmetric hydrogenation is carried out using an optically active ruthenium-phosphine complex as a catalyst.

[0008]

[Chemical 8]

(In the formula, R ¹ and R ² have the same meanings as described above.) The optically active 3-N-acylamino-3
-Provides a process for the production of substituted alkylpropionic acids.

[0010] The present invention is represented by the general formula (I) and (Z) -3-N- acylamino-3-substituted alkyl luer click <br/> Lil acids, optically active ruthenium - phosphine complex Asymmetric hydrogenation is carried out as a catalyst to obtain an optically active 3-N-acylamino-3-substituted alkylpropionic acid represented by the above general formula (II), and the obtained optically active 3-N-
General formula (III) characterized by deacylating an acylamino-3-substituted alkylpropionic acid

[0011]

[Chemical 9]

(In the formula, R ² has the same meaning as described above.)
The present invention provides a method for producing an optically active β-amino acid represented by

The (Z) -3-N-acylamino-3-substituted alkyl represented by the above general formula (I), which is a raw material of the present invention, is used.
The luer acrylic acids, for example, (Z)-3-benzamide-2-hexenoic acid, (Z)-3-benzamido-4
Methyl-2-pentenoic acid, (Z) -3-acetamido-4
-Methyl-2-pentenoic acid, (Z) -3-benzamide-
4-phenyl-2-butenoic acid, (Z) -3-acetamido-4-phenyl-2-butenoic acid, (Z) -3-benzamido-4-methoxycarbonyl-2-butenoic acid, (Z) -3
-Acetamido-4-methoxycarbonyl-2-butenoic acid, (Z) -3-benzyloxycarboxamide-4-methoxycarbonyl-2-butenoic acid and the like can be mentioned.

In the present invention, the optically active ruthenium-phosphine complex used as a catalyst includes those represented by the following general formula (IV), (V) or (VII). RuHCl (R ⁴ −BINAP) ₂ (IV) [RuH (R ⁴ −BINAP) ₂ ] Y (V) [Ru (R ⁴ −BINAP)] (O ₂ CR ⁵ ) ₂ (VII) [wherein R ⁴ −BINAP is formula (VI)

[0015]

[Chemical 10]

(In the formula, R ⁴ represents a hydrogen atom or a lower alkyl group), which represents a tertiary phosphine, and Y represents B
F ₄ ⁻ , PF ₆ ⁻ , ClO ₄ ⁻ or SbF ₆ ⁻ is shown, and R ⁵ is a lower alkyl group. Among the complexes represented by the above general formula (IV), a complex in which R ⁴ -BINAP is a tertiary phosphine represented by the above formula (VI) and R ⁴ is a hydrogen atom or a methyl group [RuHCl (R ⁴ −
BINAP) ₂ ] is J. Chem. Soc., Chem. Commun., 1985, 92.
2-924, and as disclosed in JP-61-63690, JP-ruthenium black Li de and cycloocta-1,5 - obtained by heating the reaction of diene in ethanol, wherein [RuCl ₂ ( cod)] _n (wherein cod is cycloocta-
1,5 - diene, n represents a compound represented by the number of positive), 2,2'-bis (di -p-R ⁴ - phenyl e Sufino) -
It can be obtained by heating and reacting 1,1′-binaphthyl (R ⁴ -BINAP) in an ethanol solvent in the presence of a tertiary amine.
In the above production method, an optically active ruthenium-phosphine complex can be prepared by using optically active R ⁴ -BINAP. Examples of the complex thus obtained include the following.

RuHCl (BINAP) ₂ , RuHCl (Tol-BINAP)
₂ (in the above formulas, BINAP is 2,2'-bis (diphenyl e Sufino) -1,1'-binaphthyl, Tol-BINAP is 2,2'-bis (di -p- tolyl e Sufino) -1,1 In the complex represented by the general formula (V), R ⁴
-BINAP is a tertiary phosphine represented by the above formula (VI) and a complex in which R ⁴ is a hydrogen atom or a methyl group [RuH (R ⁴ -BINAP) ₂ ] Y
By the method reported in J. Organometal. Chem., 1992, 428, 155-167. [RuH (Me ₂ NNH ₂ ) ₃ (cod)]
PF ₆ (wherein, cod is cycloocta-1,5 - diene, Me represents a methyl group) with a compound represented by 2,2'-bis (di -p-R ⁴ - phenyl e Sufino) -1 It is prepared by reacting 1,1′-binaphthyl (R ⁴ -BINAP) in ethanol or by the method disclosed in JP-A-63-41487. In the above production method, an optically active ruthenium-phosphine complex can be prepared by using optically active R ⁴ -BINAP. Examples of the complex thus obtained include the following.

[RuH (BINAP) ₂ ] BF ₄ , [RuH (Tol−BINAP) ₂ ] BF ₄ , [RuH (BINAP) ₂ ] PF ₆ , [RuH (Tol−BINAP) ₂ ] PF ₆ , [RuH ( BINAP) ₂ ] SbF ₆ , [RuH (Tol−BINAP) ₂ ] SbF ₆ , [RuH (BINAP) ₂ ] ClO ₄ , [RuH (Tol−BINAP) ₂ ] ClO ₄ (where BINAP is 2, 2 '-. bis (diphenyl e Sufino) -1,1'-binaphthyl, Tol-BINAP represents 2,2'-bis (di -p- tolyl e Sufino) -1,1'-binaphthyl) the above formula Among the complexes represented by (VII), R ⁴
-BINAP is a tertiary phosphine represented by the above formula (VI) and R ⁴
A complex in which is a hydrogen atom or a methyl group is disclosed in Japanese Patent Application No. Sho 61-108888.
Method disclosed in Japanese Patent Publication No. or Inorg. Chem.,
It can be obtained according to the method described in 1988, 27, 566-569. That is, the formula Ru ₂ Cl ₄ (R ⁴ −BINAP) ₂ (N
Et ₃ ) (This is the method disclosed in JP-A-61-63690, or J. Chem. Soc. Chem. Commun., 1985,
922-924) is used as a raw material, and this and a carboxylic acid salt are reacted in an alcohol solvent such as methanol, ethanol, or t-butanol under heating under reflux for 12 hours. , The target complex can be obtained. In the above production method, optically active R ⁴
-By using BINAP, optically active ruthenium-
Phosphine complexes can be prepared. Examples of the complex thus obtained include the following.

[Ru (BINAP)] (O ₂ CC (CH ₃ ) ₃ ) ₂ , [Ru (Tol-BINAP)] (O ₂ CC (CH ₃ ) ₃ ) ₂ [Ru (BINAP)] (O ₂ CCH _{3) 2,} [Ru (Tol-BINAP)] (O ₂ CCH _{3) 2} (in the formula, BINAP is 2,2'-bis (diphenyl e Sufino) -1,1'-binaphthyl, the Tol-BINAP 2 to implement the 2'-bis shows a (di -p- tolyl e Sufino) -1,1'-binaphthyl.) the present invention is a stainless steel autoclave and the reaction vessel is represented by the general formula (I) 3-N-acylamino-3 having a prochiral (Z) -configuration
- a substituted alkylene luer acrylic acid, relative to the (Z) -3-N- acylamino-3-substituted alkylene luer acrylic acids,
1 to 1/10000 times equivalents, preferably 1/100 times equivalents of the optically active ruthenium-phosphine complex is applied in a methanol or ethanol solvent alone or in a mixed solvent of these and tetrahydrofuran under a hydrogen pressure of 5 to 100 atm.
The reaction temperature is room temperature to 100 ° C, preferably 50 ° C, and 1 to 10
Stirring is carried out for 0 hours, preferably 24 hours. After the reaction, the solvent is distilled off, and the residue is subjected to silica gel column chromatography or the back extraction method to remove the complex catalyst to give the desired optically active 3-N- represented by the general formula (II). Acylamino-3-substituted alkylpropionic acid can be obtained in quantitative yield.

The optically active 3-N-acylamino-3 represented by the general formula (II) obtained as described above.
-Substituted alkylpropionic acid is subjected to a deacylation reaction such as debenzoylation or deacetylation using an acid such as hydrochloric acid by a conventional method, and further treated with an ion exchange resin or the like to give a compound represented by the general formula (III ) It is possible to obtain an optically active free β-amino acid represented by

[0021]

EXAMPLES Next, the present invention will be described with reference to production examples and examples of optically active ruthenium-phosphine complexes. The analyzes in the examples were carried out using the following analytical instruments.・ High-performance liquid chromatography: Shimadzu LC-9A (manufactured by Shimadzu Corporation) Column: CHI RALCEL OJ, 25cm × 0.46cm ID (manufactured by Daicel Chemical Industries Ltd.) CHI RALCEL OD, 25cm × 0.46cm ID (Daicel Chemical Industries Ltd Company made) Detector: UV detector, Shimadzu SPA-6A (made by Shimadzu Corporation) ・¹ H-NMR: AM-500 NMR SPECTROMETER (made by Brucker) Internal standard: Tetramethylsilicon ・ Polarimeter: DIP- Model 360 (manufactured by JASCO Corporation) -Melting point measuring device: Yanaco Mp-500D (manufactured by Yanagimoto Seisakusho) Production Example 1 Di [2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] hydridochlor Ruthenium [RuHCl ((+)-BI
NAP) ₂ ]: In a nitrogen atmosphere, a compound of the formula [RuCl ₂ (cod)] _n (in the formula, cod is cycloocta-1,5-diene, n is a positive number) 146 mg (0.521) mmol), (+)-2,2'-bis (diphenyl e Sufino) -1,1'-binaphthyl (hereinafter (+)
650 mg (1.04 mmol) of (-BINAP) was placed in a Schlenk tube, 15 ml of ethanol and 1 ml of triethylamine were added, and the mixture was heated under reflux for 3 hours to carry out the reaction. After completion of the reaction, the yellow precipitate was collected by filtration, washed once with 5 ml of ethanol and three times with 5 ml of ether, and dried by filtration under pressure. Dissolve the obtained yellow solid in methylene chloride, remove impurities by filtration, and add ether to add 369 mg (51% yield).
Yellow solid of RuHCl ((+)-BINAP) ₂ was obtained.

Elemental analysis value: C ₈₈ H ₆₅ ClP ₄ Ru theoretical value (%): C 78.9, H 5.4 Actual measurement value (%): C 78.7, H 5.5 Production Example 2 Di [2,2'-bis (diphenyl) synthesis of phosphino) -1,1'-binaphthyl] hydrido ruthenium hexafluorophosphate {[RuH ((+) -BINAP) _{2] PF 6}:... J.} Chem Soc, Dalton Trans, 1977, in 1809. reported obtained by the method 1,5 - cyclooctadiene tris (dimethylhydrazine) hydride ruthenium hexamethylene <br/> fluoride ii phosphate _{{[RuH (Me 2 NNH 2) 3} (cod) ] PF _6}
0.242 g (0.45 mmol), (+)-BINAP 0.566 g (0.91
(mmol) was placed in a Schlenk tube under a nitrogen atmosphere, 10 ml of ethanol was added, and the mixture was heated under reflux for 2 hours to carry out a reaction. After the reaction was completed, the solvent was distilled off under reduced pressure, the obtained deep red solid was dissolved in THF, and impurities were removed by filtration. Ether was added to this to give red crystals. After washing with ether several times and drying under reduced pressure, [RuH ((+)-BINAP)
₂ ] PF ₆ was obtained in an amount of 0.482 mg (yield 92%).

Elemental analysis value: Theoretical value (%) as C ₈₈ H ₆₅ P ₄ Ru: C 69.8, H 4.4 Actual value (%): C 69.4, H 4.5 Production Example 3 2,2′-bis (diphenylphosphino) ) -1,1'-Binaphtyl ruthenium dipivalate {(Ru ((−) −BINAP)] (O ₂ C
Synthesis of C (CH ₃ ) ₃ ) ₂ }: The method disclosed in JP-A-61-63690, or J.
Ru ₂ Cl ₄ ((+) −BINAP) ₂ (NEt ₃ ) 49 obtained by the method shown in Chem. Soc. Chem. Commun., 1985, 922-924.
0 mg (0.29 mmol) and potassium pivalate 352 mg (4.4 mmol)
Was placed in a Schlenk tube, the atmosphere was replaced with argon, and 36 ml of t-butanol was added. The reaction was carried out for 12 hours under heating under reflux. After completion of the reaction, the reaction solvent was distilled off, and the dried residue was extracted three times with 10 ml of ethyl ether, and then the ethyl ether was distilled off to obtain a yellow-brown crude [Ru ((-)-BINAP) ]
(O ₂ CC (CH ₃ ) ₃ ) ₂ was obtained. This was recrystallized from toluene / hexane to obtain 160 mg (yield 30%) of yellowish brown crystals.

[0024] Example 1 (3S) - (+) -3- benzamide hexanoic acid and (3S) - (+) -3- stainless steel autoclave manufacturing 50ml Ami Nohe hexanoic acid (Z)-3-benzamide - 2-Hexenoic acid 58 mg (0.25 mmol) and [RuH ((+)-BINAP) ₂ ] PF ₆ 3.7 mg (0.0025 mm) synthesized in Preparation Example 2
ol) and nitrogen substitution, tetrahydrofuran 1.25m
1 and 1.25 ml of methanol were added and the reaction was carried out at a hydrogen pressure of 5 atm and a reaction temperature of 50 ° C. for 24 hours. After completion of the reaction, the solvent was distilled off to obtain 61 mg of a crude product. 10 ml of saturated sodium bicarbonate water
After being dissolved in 10 ml of chloroform and washed with 10 ml of chloroform, the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then, the extraction operation was performed three times with 20 ml of chloroform. After drying with magnesium sulfate, chloroform was distilled off to obtain 58 mg of (3S)-(+)-3-benzamidohexanoic acid as a white solid.・ Melting point: 151-152 ° C ・¹ H-NMR (CDCl ₃ ) δppm: 0.95 (t, J = 7.4Hz, 3H), 1.39
-1.45 (m, 2H), 1.61-1.69 (m, 2H), 2.59 (dd, J = 15.8Hz, J =
5.2Hz, 1H), 4.41-4.44 (m, 1H), 7.35-7.45 (m, 2H), 7.49-
7.52 (m, 1H), 7.76-7.78 (m, 2H) . After the reaction, the solvent was distilled off and the crude product obtained was measured by ¹ H-NMR, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

The obtained carboxylic acid was subjected to high performance liquid chromatography (column: CHIRALCEL OJ, developing solvent:
Hexane / ethanol = 15/1, 0.1% formic acid added, flow rate: 1.0 ml / min., Detection: UV detector, λ = 254 nm, temperature: room temperature) As a result of analysis, the ratio of enantiomers was 91.
It was found to be 5: 8.5, and the hydrogenated product; (3S)-(+)-3-benzamidohexanoic acid was found to have an optical purity of 83% ee. The carboxylic acid obtained has an optical rotation of [α] _D = 4
6.9 ° (c = 0.81, H ₂ O), and absolute configurations are Examples 2 to 5
It is inferred to be the S form by comparison with the result of the asymmetric hydrogenation reaction of.

30 mg of the hydrogenated product obtained, 5 ml of 6N hydrochloric acid
The mixture was heated to reflux and stirred for 48 hours. The carboxylic acid hydrochloride obtained by concentration was dissolved in water, and a cationic ion exchange resin (SIGMA: AM) prepared as shown below was prepared.
BERLITE CG-120) (preparation of ion exchange resin:
2 for an appropriate amount (about 10cc) of cationic ion exchange resin
After passing 100 ml of N hydrochloric acid, 300 ml of purified water was passed. Pour 300 ml of purified water, then 100 ml of 2N NH ₃ water,
Free β- amino acid by concentrating a fraction of 2N NH ₃ water; (3S) - (+) -3- give the amino Nohe hexanoic acid.

Example 2 Preparation of (3S)-(−)-3-benzamido-4-methylpentanoic acid and (3S)-(−)-3-amino-4-methylpentanoic acid In a 50 ml stainless autoclave ( Z) -3-benzamido-4-methyl-2-pentenoic acid 40 mg (0.17 mmol)
And [RuH ((+) −BINAP) ₂ ] PF ₆ 2.5 synthesized in Production Example 2 with
Add mg (0.0017 mmol), replace with nitrogen, add 0.85 ml of tetrahydrofuran and 0.85 ml of methanol, and add hydrogen at 5
The reaction was carried out at atmospheric pressure and a reaction temperature of 50 ° C. for 24 hours. After the reaction was completed, the solvent was distilled off to obtain 43 mg of a crude product. This was dissolved in 10 ml of saturated aqueous sodium hydrogen carbonate, washed with 10 ml of chloroform, and then the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then, the extraction operation was performed three times with 20 ml of chloroform. After drying with magnesium sulfate, chloroform was distilled off to obtain 40 mg of a white solid (3S)-(-).
-3-benzamido-4-methylpentanoic acid was obtained.・ Melting point: 188 to 189 ° C ・¹ H-NMR (CDCl ₃ + CD ₃ OD) δppm: 0.90 (d, J = 6.7Hz, 3
H), 0.91 (d, J = 6.8Hz, 3H), 1.90 (septet, J = 6.8Hz, 1H),
2.52 (dd, J = 15.1Hz, J = 5.8Hz, 1H), 2.55 (dd, J = 15.1Hz, J =
5.4Hz, 1H), 4.13 (m, 1H), 7.31-7.36 (m, 2H), 7.39-7.43
(m, 1H), 7.64-7.69 (m, 2H) . After the reaction, the solvent was distilled off and the crude product obtained was measured by ¹ H-NMR, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

The obtained carboxylic acid was subjected to high performance liquid chromatography (column: CHIRALCEL OJ, developing solvent:
Hexane / ethanol = 15/1, 0.1% formic acid added, flow rate: 1.0 ml / min., Detection: UV detector, λ = 254 nm, temperature: room temperature) As a result of analysis, the ratio of enantiomers was 91:
It was found that the hydrogenated product; (3S)-(-)-3-benzamido-4-methylpentanoic acid had an optical purity of 82% ee. The absolute configuration of the obtained hydrogenated product was found to be the S form by comparing the retention times of the absorption peaks of the high performance liquid chromatography obtained in Example 10. The obtained hydrogenated product was subjected to debenzoylation reaction in the same manner as in Example 1 to give a free β-amino acid; (3S)-
(−)-3-Amino-4-methylpentanoic acid was obtained.

Example 3 Preparation of (3S)-(+)-3-acetamido-4-methylpentanoic acid and (3S)-(+)-3-amino-4-methylpentanoic acid In a 50 ml stainless autoclave ( Z) -3-acetamidoamido-4-methyl-2-pentenoic acid 44 mg (0.25
mmol) and in Production Example 2 [RuH ((+) −BINAP) ₂ ].
3.7 mg (0.0025 mmol) of PF ₆ was added, and after purging with nitrogen, 1.25 ml of tetrahydrofuran and 1.25 ml of methanol were added and the reaction was carried out at a hydrogen pressure of 5 atm and a reaction temperature of 50 ° C. for 24 hours. After the reaction was completed, the solvent was distilled off to obtain 48 mg of a crude product. This was dissolved in 10 ml of saturated aqueous sodium hydrogen carbonate, washed with 10 ml of chloroform, and then the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then, add 3 ml with 20 ml of chloroform.
The extraction operation was performed twice. After drying with magnesium sulfate, chloroform was distilled off to obtain 40 mg of a white solid (3
S)-(+)-3-acetamido-4-methylpentanoic acid was obtained.・ Melting point: 117-118 ° C ・¹ H-NMR (CDCl ₃ ) δppm: 0.94 (d, J = 6.7Hz, 3H), 0.95
(d, J = 6.7Hz, 3H), 1.87 (octet, J = 6.9Hz, 1H), 2.53 (dd, J
= 15.7Hz, J = 6.4Hz, 2H), 2.60 (dd, J = 15.7Hz, J = 4.5Hz, 2H),
4.04-4.08 (m, 1H), 5.99 (d, J = 9.1Hz, 1H) . After the reaction, the solvent was distilled off and the crude product obtained was measured by ¹ H-NMR, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%. The obtained carboxylic acid is reacted with aniline to synthesize an amide, and high performance liquid chromatography (column: CHIRALCEL OD, developing solvent: hexane / ethanol = 50/1, flow rate: 1.0 ml / min., Detection:
(UV detector, λ = 254 nm, temperature: room temperature) analysis revealed that the ratio of enantiomers was 94.5: 5.5, and the hydrogenated product was (3S)-(+)-3-acetamido-4-methyl. It was found that pentanoic acid had an optical purity of 89% ee. A mixture of 30 mg of the obtained hydrogenated product and 5 ml of 2N hydrochloric acid was stirred under heating under reflux for 48 hours. The carboxylic acid hydrochloride obtained by concentration was dissolved in water to prepare a cationic ion exchange resin (SIGMA: AMBERLITE) prepared as shown in Example 1.
CG-120). Pour 300 ml of purified water, then 2
100 ml of NH ₃ water was poured, and the fraction of 2N NH ₃ water was concentrated to give free β-amino acid; (3S) − (+)
-3-Amino-4-methylpentanoic acid was obtained. The optical rotation of this compound was measured. [Α] _D = 37 ° (c = 0.81, H
₂ O) and its absolute configuration was found to be S-form.

Example 4 Production of (3S)-(+)-3-acetamido-4-phenylbutanoic acid and (3S)-(+)-3-amino-4-phenylbutanoic acid In a 50 ml stainless steel autoclave ( Z) -3-Acetamido-4-phenyl-2-butenoic acid 51 mg (0.25 mmol)
And [RuH ((+)-BINAP) ₂ ] PF ₆ 3.7 synthesized in Production Example 2 and
Add mg (0.0025 mmol), replace with nitrogen, add 1.25 ml of tetrahydrofuran and 1.25 ml of methanol, and add hydrogen at 5
The reaction was carried out at atmospheric pressure and a reaction temperature of 50 ° C. for 24 hours. After completion of the reaction, the solvent was distilled off to obtain 55 mg of a crude product. Silica gel column chromatography (developing solvent: chloroform /
The crude product was purified with methanol = 10/1) and
Obtained was mg (3S)-(+)-3-acetamido-4-phenylbutanoic acid as a white solid. Melting ^{point: 139~140 ℃ · 1 H-NMR} (CDCl 3 + CD 3 OD) δppm: 1.96 (s, 3H), 2.51 (d
d, J = 16.4Hz, J = 5.5Hz, 1H), 2.60 (d, J = 16.4Hz, J = 5.2Hz, 1
H), 2.88 (dd, J = 13.7Hz, J = 8.0Hz, 1H), 2.97 (dd, J = 13.7H
z, J = 6.5Hz, 1H), 4.49-4.51 (m, 1H), 6.08 (d, J = 7.9Hz, 1
H), 7.11-7.36 (m, 5H) . After the reaction, ¹ H-NMR of the crude product obtained by distilling the solvent off was measured, and it was found that only the desired hydrogenated product and the starting material were obtained at a conversion rate of 53%.

For the obtained carboxylic acid, high performance liquid chromatography (column: CHIRALCEL OJ, developing solvent:
(Hexane / ethanol = 15/1, 0.1% formic acid added, flow rate: 1.0 ml / min., Detection: UV detector, λ = 254 nm, temperature: room temperature) As a result of analysis, the ratio of enantiomers was 92.
It was 5: 7.5, and it was found that the hydrogenated product; (3S)-(+)-3-acetamido-4-phenylbutanoic acid had an optical purity of 85% ee. Further, the obtained hydrogenated product was subjected to a deacetylation reaction in the same manner as in Example 3 to give free β-
Amino acid; (3S)-(+)-3-amino-4-phenylbutanoic acid was obtained. When the optical rotation of this compound was measured
[α] _D = 16 ° (c = 0.60, H ₂ O) and its absolute configuration is S
It turned out to be the body.

Example 5 Preparation of (3S)-(+)-3-benzamido-4-phenylbutanoic acid and (3S)-(+)-3-amino-4-phenylbutanoic acid In a 50 ml stainless steel autoclave ( Z) -3-Benzamido-4-phenyl-2-butenoic acid 70 mg (0.25 mmol)
And [RuH ((+)-BINAP) ₂ ] PF ₆ 3.7 synthesized in Production Example 2 and
Add mg (0.0025 mmol), replace with nitrogen, add 1.25 ml of tetrahydrofuran and 1.25 ml of methanol, and add hydrogen at 5
The reaction was carried out at atmospheric pressure and a reaction temperature of 50 ° C. for 24 hours. After the reaction was completed, the solvent was distilled off to obtain 74 mg of a crude product. Silica gel column chromatography (developing solvent: chloroform /
Purify the crude product with methanol = 7/1)
Obtained was mg of a white solid, (3S)-(+)-3-benzamido-4-phenylbutanoic acid.・ Melting point: 168 to 170 ° C. ・¹ H-NMR (CDCl ₃ + d-6 DMSO) δppm: 2.53 (dd, J = 16.1
Hz, J = 4.5Hz, 1H), 2.61 (dd, J = 16.1Hz, J = 4.5Hz, 1H), 2.94
(dd, J = 13.8Hz, J = 8.5Hz, 1H), 3.11 (dd, J = 13.8Hz, J = 6.1H
z, 1H), 4.61-4.69 (m, 1H), 7.19 (m, 8H), 7.14-7.77 (m, 2
H) . After the reaction, the solvent was distilled off and the crude product obtained was measured by ¹ H-NMR, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

The obtained carboxylic acid is reacted with diazomethane to synthesize a methyl ester, which is then subjected to high performance liquid chromatography (column: CHIRALCEL OJ, developing solvent: hexane / 2-propanol = 10/1, flow rate: 1.0 ml / min). ., Detection: UV detector, λ = 254 nm, temperature: room temperature) analysis revealed that the ratio of enantiomers was 90.5: 9.5, hydrogenated product; (3S)-(+)-3-benzamide It was found that -4-phenylbutanoic acid had an optical purity of 81% ee. Further, the absolute configuration of the obtained hydrogenated product was found to be the S form by comparing the retention times of the absorption peaks of the high performance liquid chromatography obtained in Example 11. The obtained hydrogenated product was subjected to a debenzoylation reaction in the same manner as in Example 1 to obtain a free β-amino acid; (3S)-(+)-3-amino-4-phenylbutanoic acid.

Example 6 Preparation of (3R)-(+)-3-acetamido-4-methoxycarbonylbutanoic acid (Z) -3-acetamido-4-methoxycarbonyl-2-butenoic acid 50 mg in a 50 ml stainless steel autoclave.
(0.25 mmol) and [RuH ((+)-BINA]
P) ₂ ) PF ₆ 3.7 mg (0.0025 mmol) was added, and after nitrogen substitution,
Tetrahydrofuran (1.25 ml) and methanol (1.25 ml) were added and the reaction was carried out at a hydrogen pressure of 5 atm and a reaction temperature of 50 ° C. for 24 hours. After the reaction was completed, the solvent was distilled off to obtain 54 mg of a crude product. Dissolve this in 10 ml of saturated aqueous sodium hydrogen carbonate, and add 10 ml of chloroform.
After washing with, the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then chloroform 20
Extraction was performed 3 times with ml. After drying with magnesium sulfate, chloroform was distilled off to obtain 50 mg of a white solid.
(3R)-(+)-3-acetamido-4-methoxycarbonylbutanoic acid was obtained.・ Melting point: 133.5 to 134.0 ° C ・¹ H-NMR (CDCl ₃ ) δppm: 1.91 (s, 3H), 2.59 (d, J = 6.9
Hz, 2H), 2.60 (dd, J = 15.6Hz, J = 7.3Hz, 1H), 2.65 (dd, J = 1
5.6Hz, J = 6.0Hz, 1H), 3.66 (s, 3H), 4.52 (quintet, J = 6.6H
z, 1H) . Optical rotation α = 0.007 ° (CHCl ₃ ) From the sign of optical rotation, the absolute configuration of the obtained carboxylic acid is R
It turned out to be the body. After the reaction, the solvent was distilled off and the crude product obtained was subjected to ¹ H-NMR measurement, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

The obtained carboxylic acid and (R)-(+)-α-
React with phenylethylamine to synthesize amide,
As a result of ¹ H-NMR measurement, the ratio of the diastereomers was 89.5: 10.5 based on the absorption area ratio of the two diastereomers. Therefore, the hydrogenated product, (3R)-(+)-3-acetamide, was used. -4-Methoxycarbonylbutanoic acid has an optical purity of 79%
It turned out to be ee.

Example 7 Preparation of (3R)-(+)-3-benzamido-4-methoxycarbonylbutanoic acid In a 50 ml autoclave made of stainless steel, 66 mg of (Z) -3-belluzamido-4-methoxycarbonyl-2-butenoic acid.
(0.25 mmol) and [RuH ((+)-BINA]
P) ₂ ) PF ₆ 3.7 mg (0.0025 mmol) was added, and after nitrogen substitution,
Tetrahydrofuran (1.25 ml) and methanol (1.25 ml) were added and the reaction was carried out at a hydrogen pressure of 5 atm and a reaction temperature of 50 ° C. for 24 hours. After the reaction was completed, the solvent was distilled off to obtain 70 mg of a crude product. Dissolve this in 10 ml of saturated aqueous sodium hydrogen carbonate, and add 10 ml of chloroform.
After washing with, the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then chloroform 20
Extraction was performed 3 times with ml. After drying with magnesium sulfate, chloroform was distilled off to obtain 66 mg of a white solid.
(3R)-(+)-3-benzamido-4-methoxycarbonylbutanoic acid was obtained.・ Melting point: 118-124 ℃ ・¹ H-NMR (CDCl ₃ ) δppm: 2.76 (dd, J = 16.4Hz, J = 6.1H
z, 1H), 2.76 (dd, J = 6.7Hz, 3H), 2.85 (dd, J = 16.4Hz, J = 5.4
Hz, 1H), 2.86 (dd, J = 16.4Hz, J = 5.4Hz, 1H), 3.70 (s, 3H),
4.80-4.83 (m, 1H), 7.41 (t, J = 97.4Hz, 2H), 7.49 (t, J = 7.4
Hz, 1H), 7.76 (d, J = 7.4Hz, 2H) . Optical rotation [α] _D = 5.2 ° (c = 0.6, CHCl ₃ ) From the sign of optical rotation, the absolute configuration of the carboxylic acid obtained is R
It turned out to be the body. After the reaction, the solvent was distilled off and the crude product obtained was measured by ¹ H-NMR, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

High performance liquid chromatography (column: CHIRALCEL OJ, developing solvent: hexane / ethanol = 10/1, 0.1% formic acid added, flow rate:
1.0 ml / min, detection: UV detector, λ = 254 nm, temperature:
As a result of analysis, the ratio of enantiomers was 93: 7, and the hydrogenated product; (3R)-(+)-3-benzamido-4-methoxycarbonylbutanoic acid had an optical purity of 86% ee. I knew it was.

[0038] Example 8 (3S) - (+) -3- benzyloxy-carboxaldehyde Into a stainless steel autoclave of manufacturing 50ml of bromide 4-methoxycarbonyl butanoic acid (Z)-3-benzyloxy-carboxamide-4-methoxycarbonyl - Two
Synthesized in Preparation Example 2 with 73 mg (0.25 mmol) of butenoic acid [Ru
After adding 3.7 mg (0.0025 mmol) of H ((+)-BINAP) ₂ ] PF _{6 and} replacing with nitrogen, 1.25 ml of tetrahydrofuran and 1.25 ml of methanol were added, and the hydrogen pressure was 50 atm and the reaction temperature was 50 ° C.
The reaction of time was carried out. After the reaction was completed, the solvent was distilled off to give 77 mg.
The crude product of was obtained. This was dissolved in 10 ml of saturated aqueous sodium hydrogen carbonate, washed with 10 ml of chloroform, and then the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. afterwards,
Extraction operation was performed three times with 20 ml of chloroform. After drying with magnesium sulfate, chloroform was distilled off to obtain 73 mg of (3S)-(+)-3-benzyloxycarboxamide-4-methoxycarbonylbutanoic acid as a white solid.・ Melting point: 95-96 ° C ・¹ H-NMR (CDCl ₃ ) δppm: 0.94 (d, J = 6.7Hz, 3H), 0.95
(d, J = 6.7Hz, 3H), 1.87 (octet, J = 6.9Hz, 1H), 2.53 (dd, J
= 15.7Hz, J = 6.4Hz, 2H), 2.60 (dd, J = 15.7Hz, J = 4.5Hz, 2H),
4.04-4.08 (m, 1H), 5.99 (d, J = 9.1Hz, 1H) . Optical rotation α = 0.005 ° (CHCl ₃ ) From the sign of optical rotation, the absolute configuration of the obtained carboxylic acid is S
It turned out to be the body. After the reaction, the solvent was distilled off, and the crude product obtained was measured by ¹ H-NMR, and the conversion rate was 70%.
It was found that the desired hydrogenation product and raw material were obtained in.

The resulting carboxylic acid and (R)-(+)-α-
React with phenylethylamine to synthesize amide,
As a result of ¹ H-NMR measurement, the ratio of the diastereomers was 96.5: 3.5 based on the absorption area ratio of the two diastereomers. Therefore, the hydrogenated product; (3S)-(+)-3-benzyl. Oxycarboxamide-4-methoxycarbonylbutanoic acid was found to have an optical purity of 93% ee.

Example 9 Preparation of (3R)-(−)-3-benzamidohexanoic acid (Z) -3-benzamido-2-hexenoic acid (58 mg, 0.25 mmol) was prepared in a 50 ml stainless autoclave and prepared in Preparation Example 3. (Ru ((−) −BINAP)) (O ₂ CC (CH ₃ ) ₃ ) ₂ 2.5 mg (0.
(25 mmol) was added and, after purging with nitrogen, 2.5 ml of methanol was added and the reaction was carried out for 24 hours at a hydrogen pressure of 5 atm and a reaction temperature of 50 ° C. After the reaction was completed, the solvent was distilled off to obtain 60 mg of a crude product. Dissolve this in 10 ml of saturated aqueous sodium hydrogen carbonate, and add chloroform.
After washing with 10 ml, the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then, the extraction operation was performed three times with 20 ml of chloroform. After drying with magnesium sulfate, chloroform was distilled off to obtain 58 mg of (3R)-(-)-3-benzamidohexanoic acid as a white solid.・ Melting point: 151-152 ° C ・¹ H-NMR (CDCl ₃ ) δppm: 0.95 (t, J = 7.4Hz, 3H), 1.39
-1.45 (m, 2H), 1.61-1.69 (m, 2H), 2.59 (dd, J = 15.8Hz, J =
5.2Hz, 1H), 4.41-4.44 (m, 1H), 7.35-7.45 (m, 2H), 7.49-
7.52 (m, 1H), 7.76-7.78 (m, 2H) . After the reaction, the solvent was distilled off and the crude product obtained was measured by ¹ H-NMR, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

For the obtained carboxylic acid, high performance liquid chromatography (column: CHIRALCEL OJ, developing solvent:
Hexane / ethanol = 15/1, 0.1% formic acid added, flow rate: 1.0 ml / min., Detection: UV detector, λ = 254 nm, temperature: room temperature) As a result of analysis, the ratio of enantiomers was 86:
14 and the hydrogenated product; (3R)-(−)-3-benzamidohexanoic acid was found to have an optical purity of 72% ee. Further, the absolute configuration of the obtained carboxylic acid was found to be the R-form by comparing the retention times of the absorption peaks of the high performance liquid chromatography obtained in Example 1.

Example 10 Preparation of (3R)-(+)-3-benzamido-4-methylpentanoic acid (Z) -3-benzamido-4-methyl-2-pentenoic acid 40 mg (0.17) in a 50 ml stainless steel autoclave. mmol)
[Ru ((−) −BINAP)] (O ₂ CC (CH ₃ )
₃ ) ₂ 1.7 mg (0.0017 mmol) was added, and after nitrogen substitution, 1.7 ml of methanol was added, and the hydrogen pressure was 5 atm and the reaction temperature was 50 ° C.
The reaction was carried out for 24 hours. After the reaction was completed, the solvent was distilled off and 42
Obtained mg of crude product. Dissolve this in 10 ml of saturated sodium bicarbonate water,
After washing with 10 ml of chloroform, the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then, the extraction operation was performed three times with 20 ml of chloroform. After drying over magnesium sulfate, the chloroform was distilled off,
Obtained was mg (3R)-(+)-3-benzamido-4-methylpentanoic acid as a white solid.・ Melting point: 188 to 189 ° C ・¹ H-NMR (CDCl ₃ + CD ₃ OD) δppm: 0.90 (d, J = 6.7Hz, 3
H), 0.91 (d, J = 6.8Hz, 3H), 1.90 (septet, J = 6.8Hz, 1H),
2.52 (dd, J = 15.1Hz, J = 5.8Hz, 1H), 2.55 (dd, J = 15.1Hz, J =
5.4Hz, 1H), 4.13 (m, 1H), 7.31-7.36 (m, 2H), 7.39-7.43
(m, 1H), 7.64-7.69 (m, 1H) . After the reaction, the solvent was distilled off and the crude product obtained was subjected to ¹ H-NMR measurement, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

For the obtained carboxylic acid, high performance liquid chromatography (column: CHIRALCEL OJ, developing solvent:
Hexane / ethanol = 15/1, 0.1% formic acid added, flow rate: 1.0 ml / min., Detection: UV detector, λ = 254 nm, temperature: room temperature)) As a result of analysis, the ratio of enantiomers was 9
It was found to be 1: 9, and the hydrogenated product; (3R)-(+)-3-benzamido-4-methylpentanoic acid was found to have an optical purity of 82% ee. The hydrogenated product obtained was 30 mg, 6
A mixture of 5 ml of N hydrochloric acid was stirred under heating under reflux for 48 hours.
It was Dissolve the carboxylic acid hydrochloride obtained by concentration in water
And the cationic ion prepared as shown in Example 1
It was filled in an exchange resin (SIGMA: AMBERLITE CG-200). purified water
Pour 300 ml, then 100 ml of 2N NH ₃ water and 2N NH ₃
By concentrating the water fraction, the free β-
Minoic acid; (3R)-(-)-3-amino-4-methylpenta
The acid was obtained. When the optical rotation of this compound was measured,
[Α] _D = −27.45 ° (c = 0.51, H ₂ O)
The table was found to be R-shaped.

Example 11 Production of (3R)-(−)-3-benzamido-4-phenylbutanoic acid and (3R)-(−)-3-amino-4-phenylbutanoic acid In a 50 ml stainless steel autoclave ( Z) -3-Benzamido-4-phenyl-2-butenoic acid 70 mg (0.25 mmol)
[Ru ((−) −BINAP)] (O ₂ CC (CH ₃ )
₃ ) ₂ 2.5 mg (0.0017 mmol) was added, and after nitrogen substitution, 2.5 ml of methanol was added and added, hydrogen pressure was 5 atm, reaction temperature was 50 ° C.
The reaction was carried out for 24 hours. After the reaction is completed, the solvent is distilled off
73 mg of crude product was obtained. Silica gel column chromatography (developing solvent: chloroform / methanol = 7 /
The crude product was purified according to 1) to obtain 70 mg of (3R)-(-)-3-benzamido-4-phenylbutanoic acid as a white solid.・ Melting point: 168 to 170 ° C. ・¹ H-NMR (CDCl ₃ + d-6 DMSO) δppm: 2.53 (dd, J = 1
6.1Hz, J = 4.5Hz, 1H), 2.61 (dd, J = 16.1Hz, J = 4.5Hz, 1H),
2.94 (dd, J = 13.8Hz, J = 8.5Hz, 1H), 3.11 (dd, J = 13.8Hz, J =
6.1Hz, 1H), 4.61-4.69 (m, 1H), 7.19 (m, 8H), 7.14-7.77
(m, 2H) . After the reaction, the solvent was distilled off and the crude product obtained was measured by ¹ H-NMR, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

The obtained carboxylic acid is reacted with diazomethane to synthesize a methyl ester, which is then subjected to high performance liquid chromatography (column: CHIRALCEL OJ, developing solvent: hexane / 2-propanol = 10/1, flow rate: 1.0 ml / min). ., Detection: UV detector, λ = 254 nm, temperature: room temperature) analysis showed that the ratio of enantiomers was 88.5: 11.5, hydrogenated product; (3R)-(−)-3-benzamide It was found that -4-phenylbutanoic acid had an optical purity of 77% ee. The obtained hydrogenated product was subjected to a debenzoylation reaction in the same manner as in Example 1 to give a free β-amino acid; (3R)-(-)-
3-Amino-4-phenylbutanoic acid was obtained. When the light rotation of this compound was measured, [α] _D = 16 ° (c = 0.5, H ₂
O) and its absolute configuration was found to be R-configuration.

Example 12 Preparation of (3S)-(−)-3-acetamido-4-methoxycarbonylbutanoic acid 50 mg of (Z) -3-acetamido-4-methoxycarbonyl-2-butenoic acid was added to a 50 ml stainless steel autoclave.
(0.25 mmol) and [Ru ((−)-BINA]
P)] (O ₂ CC (CH ₃ ) ₃ ) ₂ 2.5 mg (0.0017 mmol) was added, and after nitrogen substitution, 2.5 ml of methanol was added and the hydrogen pressure was 5 atm.
The reaction was carried out at a reaction temperature of 50 ° C. for 24 hours. After the reaction was completed, the solvent was distilled off to obtain 53 mg of a crude product. Add this to saturated sodium bicarbonate water
After dissolving in 10 ml and washing with 10 ml of chloroform, the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then, the extraction operation was performed three times with 20 ml of chloroform. After drying over magnesium sulfate, chloroform was distilled off to obtain 50 mg of (3S)-(-)-3-acetamido-4-methoxycarbonylbutanoic acid as white solid.・ Melting point: 133.5 to 134.0 ° C ・¹ H-NMR (CDCl ₃ ) δppm: 1.91 (s, 3H), 2.59 (d, J = 6.9
Hz, 2H), 2.60 (dd, J = 15.6Hz, J = 7.3Hz, 1H), 2.65 (dd, J = 1
5.6Hz, J = 6.0Hz, 1H), 3.66 (s, 3H), 4.52 (quintet, J = 6.6H
z, 1H) . After the reaction, the solvent was distilled off and the crude product obtained was measured by ¹ H-NMR, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

The obtained carboxylic acid is reacted with (R) -(+)-α-phenylethylamine to synthesize an amide, and ¹ H
As a result of NMR measurement, the ratio of the diastereomers was 89.5: 10.5 based on the absorption area ratio of the two diastereomers. Therefore, the hydrogenated product (3S)-(−)-3-acetamido-4- Methoxycarbonylbutanoic acid was found to have an optical purity of 79% ee. The absolute configuration of the obtained carboxylic acid is the same as that of the carboxylic acid in Example 6 and
¹ H-NM of amide obtained by reaction with phenylethylamine
By comparing with the chemical shift value of the R absorption peak, it was found to be the S form.

Example 13 Preparation of (3S)-(−)-3-benzamido-4-methoxycarbonylbutanoic acid In a 50 ml stainless autoclave, (Z) -3-benzamido-4-methoxycarbonyl-2-butenoic acid 66 mg
(0.25 mmol) and [Ru ((−)-BINA]
P)] (O ₂ CC (CH ₃ ) ₃ ) ₂ 2.5 mg (0.0017 mmol) was added, and after nitrogen substitution, 2.5 ml of methanol was added and the hydrogen pressure was 5 atm.
The reaction was carried out at a reaction temperature of 50 ° C for 12 hours. After the reaction was completed, the solvent was distilled off to obtain 69 mg of a crude product. Add this to saturated sodium bicarbonate water
After dissolving in 10 ml and washing with 10 ml of chloroform, the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then, the extraction operation was performed three times with 20 ml of chloroform. After drying over magnesium sulfate, chloroform was distilled off to obtain 66 mg of white solid (3S)-(-)-3-benzamido-4-methoxycarbonylbutanoic acid.・ Melting point: 118-124 ℃ ・¹ H-NMR (CDCl ₃ ) δppm: 2.76 (dd, J = 16.4Hz, J = 6.1H
z, 1H), 2.76 (dd, J = 6.7Hz, 3H), 2.85 (dd, J = 16.4Hz, J = 5.4
Hz, 1H), 2.86 (dd, J = 16.4Hz, J = 5.4Hz, 1H), 3.70 (s, 3H),
4.80-4.83 (m, 1H), 7.41 (t, J = 97.4Hz, 2H), 7.49 (t, J = 7.4
Hz, 1H), 7.76 (d, J = 7.4Hz, 2H) . After the reaction, the solvent was distilled off and the crude product obtained was measured by ¹ H-NMR, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

High performance liquid chromatography (column: CHIRALCEL OJ, developing solvent: hexane / ethanol = 10/1, 0.1% formic acid added, flow rate:
1.0 ml / min., Detection: UV detector, λ = 254 nm, temperature:
As a result of analysis, a hydrogenated product; (3S)-(-)
It was found that -3-benzamido-4-methoxycarbonylbutanoic acid had an optical purity of 66% ee. The absolute configuration of the obtained carboxylic acid was determined by the high-performance liquid chromatography obtained in Example 7.
By comparing the retention times of the absorption peaks of the matography, S
It turned out to be the body.

Example 14 Preparation of (3R)-(−)-3-benzyloxycarboxamide-4-methoxycarbonylbutanoic acid In a 50 ml stainless steel autoclave, (Z) -3-benzyloxycarboxamide-4-methoxycarbonyl-2 was added.
Synthesized in Preparation Example 3 with 73 mg (0.25 mmol) of butenoic acid [Ru
((−) −BINAP)] (O ₂ CC (CH ₃ ) ₃ ) ₂ 2.5 mg (0.0017 mmol) was added, and after nitrogen substitution, 2.5 ml of methanol was added, and hydrogen pressure was 50 atm and reaction temperature was 50 ° C. The reaction was carried out for 24 hours. After the reaction was completed, the solvent was distilled off to obtain 76 mg of a crude product. This was dissolved in 10 ml of saturated aqueous sodium hydrogen carbonate, washed with 10 ml of chloroform, and the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then, add 3 ml with 20 ml of chloroform.
The extraction operation was performed twice. After drying over magnesium sulfate, the chloroform was distilled off to give 73 mg of a white solid (3R).
-(-)-3-Benzyloxycarboxamide-4-methoxycarbonylbutanoic acid was obtained.・ Melting point: 95-96 ° C ・¹ H-NMR (CDCl ₃ ) δppm: 0.94 (d, J = 6.7Hz, 3H), 0.95
(d, J = 6.7Hz, 3H), 1.87 (octet, J = 6.9Hz, 1H), 2.53 (dd, J
= 15.7Hz, J = 6.4Hz, 2H), 2.60 (dd, J = 15.7Hz, J = 4.5Hz, 2H),
4.04-4.08 (m, 1H), 5.99 (d, J = 9.1Hz, 1H) . After the reaction, the solvent was distilled off and the crude product obtained was measured by ¹ H-NMR, and it was found that only the desired hydrogenation product was obtained at a conversion rate of 100%.

The obtained carboxylic acid is reacted with (R)-(+)-α-phenylethylamine to synthesize an amide, and ¹ H
As a result of NMR measurement, the ratio of the diastereomers was 91.5: 8.5 from the absorption area ratio of the two diastereomers. Therefore, the hydrogenated product; (3R)-(−)-3-benzyloxycarboxamide It was found that -4-methoxycarbonylbutanoic acid had an optical purity of 83% ee. The absolute configuration of the obtained carboxylic acid is the same as that of the carboxylic acid in Example 8 .
Obtained by reaction with (R)-(+)-α-phenylethylamine
Of chemical shifts of ¹ H-NMR absorption peaks of selected amides
By doing so , it was found to be the R form.

Example 15 Preparation of (3R)-(+)-3-benzamido-4-methoxycarbonylbutanoic acid (Z) -3-benzamido-4-methoxycarbonyl-2-butenoic acid 66 mg in a 50 ml stainless steel autoclave.
(0.25 mmol) and RuHCl ((+)-BINA synthesized in Production Example 1)
P) ₂ 3.5 mg (0.0025 mmol) was charged, and after nitrogen substitution, 1.25 ml of tetrahydrofuran and 1.25 ml of methanol were added,
The reaction was carried out at a hydrogen pressure of 5 atm and a reaction temperature of 50 ° C. for 24 hours.
After the reaction was completed, the solvent was distilled off to obtain 70 mg of a crude product. This was dissolved in 10 ml of saturated aqueous sodium hydrogen carbonate, washed with 10 ml of chloroform, and the aqueous solution was acidified with concentrated hydrochloric acid until the hydrogen ion concentration (pH) became 1. Then, add 3 ml with 20 ml of chloroform.
The extraction operation was performed twice. After drying with magnesium sulfate, chloroform was distilled off to obtain 66 mg of a white solid (3R).
-(+)-3-Benzamido-4-methoxycarbonylbutanoic acid was obtained.・ Melting point: 118-124 ℃ ・¹ H-NMR (CDCl ₃ ) δppm: 2.76 (dd, J = 16.4Hz, J = 6.1H
z, 1H), 2.76 (dd, J = 6.7Hz, 3H), 2.85 (dd, J = 16.4Hz, J = 5.4
Hz, 1H), 2.86 (dd, J = 16.4Hz, J = 5.4Hz, 1H), 3.70 (s, 3H),
4.80-4.83 (m, 1H), 7.41 (t, J = 97.4Hz, 2H), 7.49 (t, J = 7.4
Hz, 1H), 7.76 (d, J = 7.4Hz, 2H) . After the reaction, ¹ H-NMR of the crude product obtained by distilling off the solvent was measured, and it was found that the desired hydrogenated product and the raw material were obtained at a conversion rate of 39%.

High performance liquid chromatography (column: CHIRALCEL OJ, developing solvent: hexane / ethanol = 10/1, 0.1% formic acid added, flow rate:
1.0 ml / min., Detection: UV detector, λ = 254 nm, temperature:
As a result of analysis, the ratio of enantiomers was 90:10, and the hydrogenated product; (3R)-(+)-3-benzamido-4-methoxycarbonylbutanoic acid had an optical purity of 80% ee. I knew it was. Further, the absolute configuration of the obtained carboxylic acid was found to be the R form by comparing the retention times of the absorption peaks of the high performance liquid chromatography obtained in Example 7.

[0054]

INDUSTRIAL APPLICABILITY By the method of the present invention, optically active β-amino acids, which are extremely useful as intermediates for synthesizing physiologically active peptides, important intermediates of β-lactam antibiotics, etc., with high optical purity. Obtainable.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI C07C 233/82 C07C 233/82 271/22 271/22 // C07B 53/00 C07B 53/00 B 61/00 300 61/00 300 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07C 231/12 C07C 227/20 C07C 229/08-229/14 C07C 233/45-233/47 C07C 233/82 C07C 271/22 C07B 53/00 C07B 61/00 300

Claims (4)

(57) [Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ represents a lower alkyl group, a phenyl group or a benzyloxy group. R ² represents a lower alkyl group, the hydrogen atom of which may be substituted with a phenyl group or an alkoxycarbonyl group.) chosen key (Z) -3-N- acylamino-3-substituted alkylene luer acrylic acids, optically active ruthenium - and performing asymmetric hydrogenation phosphine complex as a catalyst, the general formula (II) embedded 2] (In the formula, R ¹ and R ² have the same meanings as described above.) A method for producing an optically active 3-N-acylamino-3-substituted alkylpropionic acid. 2. A compound represented by the general formula (I): (Wherein, R ^1, R ² has. As defined above) to be represented by (Z) -3-N-acylamino-3-substituted alkyl luer click <br/> Lil acids, optically active ruthenium -Asymmetric hydrogenation is carried out using a phosphine complex as a catalyst to give a compound of general formula (II) (Wherein R ¹ and R ² have the same meanings as described above) to obtain an optically active 3-N-acylamino-3-substituted alkylpropionic acid, and further obtain the optically active 3-N -Acylamino-3-substituted alkylpropionic acid having the general formula (III) characterized by deacylating (In the formula, R ² has the same meaning as described above.) A method for producing an optically active β-amino acid. 3. An optically active ruthenium-phosphine complex having the following general formula (IV) or (V) RuHCl (R ⁴ -BINAP) ₂ (IV) [RuH (R ⁴ -BINAP) ₂ ] Y (V) [In the formula, R ⁴ -BINAP is the formula (VI). (Wherein, R ⁴ represents a hydrogen atom or a lower alkyl group.) Shows a tertiary phosphine represented by, Y is _{^{BF 4 -, PF 6 -,}} ClO 4
^- or SbF ₆ ^- shows the. ] It is what is represented by these.
Or the production method described in 2. 4. The optically active ruthenium-phosphine complex has the general formula (VII) [Ru (R ⁴ -BINAP)] (O ₂ CR ⁵ ) ₂ (VII) (wherein R ⁴ -BINAP is the same as above). And R ⁵ represents a lower alkyl group.), The production method according to claim 1 or 2.