JPH0220624B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active β-amino acids. Although many studies have been reported on methods for asymmetric synthesis of optically active α-amino acids, there are few reports on asymmetric synthesis of β-amino acids. Conventionally, as a general method for synthesizing β-amino acids, for example, α,β-
A method of nucleophilically adding an amino group to an unsaturated carboxylic acid or its ester or nitrile [e.g. J.Am.Chem.Soc., 67 , 1414 (1945)]
Arndt-
Method of induction by Eistert reaction [e.g. JCrg.
Chem., 16 , 1308 (1951)], the types of optically active α-amino acids available are limited. β−
Methods by hydrolysis of lactam compounds [e.g. J.
Org, Chem., 37, 3286 (1972)], only a product with low optical purity can be obtained. Recently, a synthetic method using the Reformatsky reaction from optically active Schiff bases was reported [Chem.Pharm.Bull., 26 , 260
(1978)], but the optical purity is low and it cannot be said to be a satisfactory method. In recent years, monocyclic β-lactam compounds with strong antibacterial activity, such as sulfazesin [Nature, 289 (12),
590 (1981)], monobactams [Nature, 291
(11), 489 (1981)] was discovered in nature, and SQ26776 as a synthetic product [RBSykes etal, 12th International Society of Chemotherapy, Lawrence, Italy (1981)].
was announced, and its usefulness as a chemotherapeutic agent is attracting attention. β-amino acids can be easily induced into monocyclic β-laccums by intramolecular dehydration condensation [e.g.
Heterocycles, 12 , 1301 (1979), Tetrah-edron
Letters, 1980 , 730, J.Am Chem.Soc., 102 ,
6161 (1980), J.Am.Chem.Soc., 103 , 2406
(1981), etc.], and can provide important synthetic intermediates such as SQ26776 (Japanese Patent Application Laid-Open No. 125362/1982). It is a well-known fact that β-amino acids have a great influence on the biological activity of amino acids, and in order to obtain β-lactams with the desired stereoisomerism and optical isomerism, it is necessary to synthesize β-amino acids with high optical purity. The present inventor focused on a method using an optically active Schiff base, and as a result of continuing various studies, it was found that when a lithiooxazoline compound is added as a carbanion to an optically active Schiff base, β- The inventors have learned that β-amino acids can be obtained with extremely high optical purity by obtaining an aminooxazoline compound and subjecting it to acid hydrolysis and then hydrogenolysis.The present invention was completed based on the above findings. The present invention is based on the formula (In the formula, R represents an aliphatic group, aromatic group, araliphatic group, alicyclic group, or heterocyclic group, *C means an optically active asymmetric carbon atom) In the production of β-amino acids, the formula (In the formula, Ph represents a phenyl group that may have a substituent, and *C has the same meaning as above.) An amino compound represented by the formula R-CHO [3] (wherein, R is the The formula obtained by reacting with an aldehyde represented by (In the formula, R and Ph mean the same groups as above,
*C has the same meaning as above) The Schiff base represented by the formula By reacting with a lithiooxazoline compound represented by the formula (In the formula, R and Ph mean the same groups as above *
C has the same meaning as above), acid hydrolyzed the compound [6], and the obtained formula (In the formula, R and Ph mean the same groups as above,
*C has the same meaning as above) is a method for producing an optically active β-amino acid, which is characterized by deα-methoxymethyl-benzylation of the compound represented by (C has the same meaning as above), and in which the compound [6] is subjected to acid hydrolysis. death,
A method for producing an optically active β-amino acid, characterized by de-α-methoxymethyl-benzylation of the obtained compound [7] by reduction, and de-α-methoxymethyl-benzylation of compound [7] by reduction. Also included is a method for producing an optically active β-amino acid characterized by the following. The above amino compound [2] is obtained by reducing optically active phenylglycine with LiAlH ₄ in an organic solvent.
formula (In the formula, Ph means the same group as above and *C means the same as above). This amino group is appropriately amino-protected, the hydroxyl group is O-methylated, and then the amino alcohol is Obtained by removing the protecting group. For example, the amino alcohol is reacted with acetic anhydride in the presence of an aqueous potassium carbonate solution to protect the amino group with an acetyl group, the optically active acetylamino alcohol obtained is reacted with NaH in an organic solvent, and then methyl iodide is added to the amino alcohol. O
-Methylation and then hydrolyzing the acetyl group with hydrochloric acid is a preferred example. The above Schiff base [4] is an amino compound [2]
is obtained by reacting with aldehyde [3]. The above reaction is carried out by a known method of forming Schiff's base from an amino and an aldehyde. It is usually carried out in an inert organic solvent such as benzene in the presence of a dehydrating agent. Examples of the aldehyde [3] include lower aliphatic aldehydes that may have branches, benzaldehyde, and cycloalkane aldehydes. Next, the Schiff base [4] obtained by the above reaction is reacted with a lithioxazoline compound [5], usually in a dry organic solvent at -45 to -80
It is carried out under cooling at °C. The lithioxazoline compound [5] can be obtained by reacting a solution of lower alkyllithium such as butyllithium in a dry organic solvent such as hexane in a solution of 2,4,4-trimethyl-2-oxazoline in a dry organic solvent such as tetrahydrofuran. It is obtained by adding a solution of the Schiff base [4] in a dry organic solvent to the resulting reaction solution and reacting it. Compound [6] thus obtained can be collected from the reaction solution by adding an aqueous solution to the reaction solution and extracting with a non-hydrophilic organic solvent. Next, compound [6] is hydrolyzed to obtain compound [7], which is usually carried out by heating with a mineral acid such as hydrochloric acid. Compound [7] is collected from the reaction solution by making the reaction solution alkaline with an alkali, washing it with a non-hydrophilic organic solvent, making the aqueous layer acidic with an acid, drying it under reduced pressure, and washing it with an organic solvent such as dichloromethane. The mother liquor is further concentrated under reduced pressure, and the water-soluble components are further concentrated under reduced pressure. This is treated with a solvent such as dichloromethane and dried to obtain compound [7]. Although it can be obtained as an amorphous solid with an acid such as the above-mentioned compound hydrochloride, if it is to be converted into a free acid, ion exchange using a cation exchange resin may be performed. Next, Compound [7] is de-α-methoxymethyl-benzylated by reduction to obtain the desired optically active β-
The amino acid is obtained by hydrogenation in an aqueous alcohol in the presence of a hydrogenation catalyst such as Pd/C. The reaction conditions may be normal pressure or under increased pressure. To collect optically active β-amino acids from the reaction solution, first remove the catalyst, concentrate the mother liquor under reduced pressure, and transfer the residue to an ion exchange resin, such as a cation exchange resin IR.
It can be separated and purified by ion exchange using -120. Next, the present invention will be specifically explained with reference to reference examples and examples, but the present invention is not limited thereto. Reference example 1 (-)-(R)-2-acetamido-2-phenylethanol (-)-(R)-2-amino-2-phenylethanol 9.62 g (0.07 mol), [α] ²² _D − 26.5゜(C=
9.0, methanol) in dichloromethane (100 ml) and 50 ml of a 20% potassium carbonate aqueous solution, 10.72 g (0.105 mol) of acetic anhydride was added dropwise over 1 hour with stirring under ice cooling. After the dropwise addition, the mixture was stirred for 15 minutes under ice cooling, and then at room temperature for 2 hours. After the reaction, the dichloromethane layer and the aqueous layer were separated, and the aqueous layer was extracted five times with 40 ml of dichloromethane. The dichloromethane layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. After treating the residue with diethyl ether,
12.31 g of colorless crystalline (-)-(R)-2-acetamido-2-phenylethanol (yield 98
%) was obtained. Melting point: 101-102.5℃ [α] ^D ₂₂ -86.9゜(C=1.05, chloroform) IR
(Nujol); 1640cm ^-1 NMR (CDCl ₃ ) δppm; 1.86 (s., 3H), 3.55~
3.93 (m., bd., repeat), 4.76-5.02 (m., 1H),
7.18 (s., 5H) Reference example 2 (-)-N-(R)-2-methoxy-1-phenylethyl]acetamide (-)-(R)-2-acetamido-2-phenylethanol 3.58g (20m A mixture of 1.10 g (23 mmol) of NaH and 5 ml of dry tetrahydrofuran was added little by little under stirring at room temperature under a nitrogen gas stream, followed by stirring for 10 hours. Gas evolved vigorously and the reaction mixture was stirred for 1 hour. A solution of 3.4 g (24 mmol) of methyl iodide in tetrahydrofuran (10 ml) was added to this at room temperature.
The mixture was added dropwise over 25 minutes and further stirred for 2 hours. The reaction mixture was poured into an ice-cooled saturated aqueous ammonium chloride solution, the organic layer was separated, and the aqueous layer was dissolved in 15 ml of diethyl ether.
After extraction three times, the organic layer was combined with the previous organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.71 g of an extract. This crystallized on standing and was recrystallized from benzene to obtain 2.05 g (yield 53%) of colorless crystalline (-)-N-[(R)-methoxy-1-phenylethyl]acetamide. Melting point; 85.5-86.5℃ [α] ²² _D -80.5゜(C=1.22, chloroform) IR
(Nujol); 1640 cm ^-1 NMR (CDCl ₃ ) δ ^TMS _ppn ; 1.95 (s., 3H), 3.28 (s.,
3H), 3.57 (d., J=5Hz), 5.10 (m., J=8Hz,
5Hz, 1H), 7.22 (s., 5H) Mass (m/z); 194 (M ⁺ +1), 193 (M ⁺ ), 148
(M ⁺ −CH ₂ OCH ₃ ), 106 (M ⁺ CH ₂ OCH ₃ −CH ₂ =
C=O) Reference example 3 (-)-(R)-2-methoxy-1-phenylethylamine (-)-N-[(R)-2-methoxy-1-phenylethyl]acetamide 10.28 g (53.2 mmol) ) to
60 ml of 3N hydrochloric acid was added, and the mixture was heated under reflux for 3.5 hours. The reaction solution was cooled and washed twice with 25 ml of diethyl ether. The aqueous layer was made alkaline with a 10% aqueous potassium hydroxide solution saturated with potassium carbonate, and diethyl ether 50%
Extracted 3 times with ml. After drying the ether layer over anhydrous magnesium sulfate, the ether was distilled off under reduced pressure. The extract of the residue is distilled under reduced pressure to obtain a colorless liquid (-)-
(R)-2-methoxy-1-phenylethylamine
5.85g (yield 73%) was obtained. Boiling point: 77-78℃/2mmHg [α] ¹⁷ _D -49.4゜(C=3.91, benzene) IR
(film); 3380, 3310, 1590 (bd) cm ^-1 NMR (CDCl ₃ ) δ ^TMS _ppn ; 1.66 (s, bd., 2H), 3.32
(s., repeat), 3.20-3.56 (m., repeat), 4.12 (d, d.
，
J=8Hz, 4Hz, 1H) Example 1 (-)-(R)-N-(3-methylbutylidene)-2-methoxy-1-phenylethylamine(-)-(R)-2-methoxy- 1.58 g (10.5 mmol) of 1-phenylethylamine in 10 ml of dry benzene
To this, 10.5 mmol (0.901 g) of isovaleraldehyde was added little by little while stirring under ice-cooling and a stream of nitrogen gas, and then 4 g of anhydrous magnesium sulfate was added.
was added and stirred for 10 hours. During this time, the temperature was gradually returned to room temperature. After the reaction, the dehydrating agent is removed and the benzene is distilled off under reduced pressure at 40°C or lower to obtain a nearly colorless liquid (-)-.
2.304 g of (R)-N-(3-methylbutylidene)-2-methoxy-1-phenylethylamine was obtained. [α] ²⁰ _D −30.6 (C = 4.03, hexane) IR (film); 1670 cm ^-1 NMR (CDCl ₃ ) δ ^TMS _ppn ; 0.91 (d., J = 7 Hz), 0.94
(d., J=7Hz) (6H), 2.18 (dd, JA=5Hz,
J _B =7Hz, 2H), 3.31 (s., ~3H), 6.61 (d., J =
6.5Hz, 2H), 4.27 (t., J = 6.5Hz, 1H), 7.27
(m., 25H), 7.68 (t., J=5Hz, 1H) Example 2 (-)-2-(2S)-2-[(1R)-2-methoxy-1-phenylethyl]amino-4- methylbentyl}-4,4-dimethyl-2-oxazoline 2,4,4-trimethyl-2-oxazoline
0.89 g (7.87 mmol) dry tetrahydrofuran
25ml) Add 15% hexane solution of butyllithium to the solution under a stream of dry nitrogen gas while stirring and cooling to -80°C.
4.8 ml (7.9 mmol) was added dropwise through a syringe over 15 minutes and stirred at -80°C for 30 minutes. -60℃
While cooling and stirring, a solution of 7.15 mmol (1.568 g) of (-)-(R)-N-(3-methylbutylidene)-2-methoxy-1-phenylethylamine in dry tetrahydrofuran (15 ml) was added. was added over 30 minutes and stirred at -65 to -60°C for 6.5 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and the organic layer and aqueous layer were separated. The aqueous layer was extracted three times with 30 ml of diethyl ether, and the extract and the previous organic layer were combined and washed with saturated brine. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to give (-)-2- as a pale yellow oil.
{(2S)-2-[1R)-2-methoxy-1-phenylethyl]amino-4-methylpentyl}-4,4
2.089 g of -dimethyl-2-oxazoline was obtained. [α] _D −85.4° (C = 3.29, hexane) IR (film); 1665 cm ^-1 NMR (CDCl ₃ ) δ ^TMS _ppn ; 0.63, 0.81 (each d., J =
6Hz, ~6H), 12.4 (s., repeat), 2.35 (d., J=
5.5Hz, 2H), 2.7 (m., 1H), 3.31 (s., repeat),
3.35 (m., repeat), 3.83 (s., 2H), 4.04 (t., J=
6.5Hz, 1H), 7.24 (m., 5H) Example 3 (-)-(3S)-3-[(1R)-2-methoxy-1
-Phenylethyl]amino-5-methylhexanoic acid (-)-2-{(2S)-2-[(1R)-2-methoxy-1-phenylethyl]amino-4-methylpentyl}-4,4-dimethyl- 2-oxazoline
30 ml of 3N hydrochloric acid was added to 2.96 g, and the mixture was heated under reflux for 4 hours. Cool the reaction mixture and add 25 ml of diethyl ether.
Washed 3 times with The aqueous layer was made alkaline with a 40% aqueous potassium hydroxide solution, saturated with potassium carbonate, and washed three times with 30 ml of diethyl ether. The aqueous layer was acidified with 3N hydrochloric acid and dried under reduced pressure. 80 ml of dichloromethane was added to the residue and filtered. The liquid was dried under reduced pressure, dissolved in 50 ml of water, filtered, and concentrated under reduced pressure. Add 80 ml of dichloromethane to the residue, dry with anhydrous magnesium sulfate,
It was concentrated under reduced pressure. Dry under reduced pressure over phosphorus pentoxide to obtain a colorless, hygroscopic, amorphous powder of (-)-(3S)-3-[(1R)
-2-methoxy-1-phenylethyl]amino-
2.437 g of 5-methylhexanoic acid hydrochloride was obtained. [α] ²⁰ _D −26.0° (C=3.15, water) NMR (D ₂ O) δ ^TMS _ppn ; 0.73 (d., J=5Hz, 6H),
1.33-1.60 (m., repeated, 3H), 2.55-3.06 (m.,
2H), 3.46 (s., repeat), 3.69-4.23 (m., 2H),
7.50 (s., 5H) The above compound was ion-exchanged using an ion-exchange resin IR-120 (elution solvent: 1.5N aqueous ammonia) to obtain a free acid. Melting point: 106.5-108.5℃ [α] ²¹ _D -41.9゜ (C=3.15, water) Example 4 (+)-(S)-3-amino-5-methylhexanoic acid (-)-(3S)-3 -[(1R)-2-methoxy-1
-Phenylethyl]amino-5-methylhexanoic acid hydrochloride (1.3 g) was dissolved in 40 ml of 50% aqueous ethanol and hydrogenated in the presence of 1.30 g of 10% PD/C under a pressure of 20 Kg/cm ² at 18°C for 20.5 hours. did. After the reaction, the catalyst was removed and the mother liquor was concentrated under reduced pressure. Charge the residue to ion exchange resin 1R-120, perform ion exchange by eluting with 1.5N ammonia water, and (+)-(S)-
546 g of 3-amino-5-methylhexanoic acid was obtained. Melting point: 211.5-212°C (decomposed) [α ²⁴ _D +27.6° (C = 2.10, water) The melting point of the product recrystallized from ethanol is 222.5-223
°C (decomposition) and [α] ²² _D +29.6° (C = 2.20, water)
has. Literature [A.Chimiak.Rocz.Chem., 43 ,
299 (1969)] Value is melting point; 223-224℃, [α] ²⁰ _D +
300° (C=2, water), it can be seen that the above product has extremely high optical purity. Example 5 (-)-(R)-N-ethylidene-2-methoxy-1-phenylethylamine 2.06 g (13.7 mmol) of (-)-(R)-2-methoxy-1-phenylethylamine was dissolved in pentane. 15ml
A solution of 0.66 g (15 mmol) of acetaldehyde distilled under ice-cooling in pentane (15 ml) was added dropwise thereto, then 4 g of anhydrous magnesium sulfate was added, and the mixture was stirred for 15 hours under ice-cooling. Filter the reaction solution,
The solution was concentrated under reduced pressure while keeping the temperature below 10 DEG C. to obtain (-)-(R)-N-ethylidene-2-methoxy-1-phenylethylamine as a colorless oil almost quantitatively. [α] ¹⁸ _D −39.5° (C=3.95, hexane) IR (film); 1665 cm ⁻¹ NMR (CDCl ₃ ) δ ^TMS _ppn ; 1.98 (d., 3H, CH ₃ −
C), 3.31 (s., 3H, OCH ₃ ), 3.40-3.83 (m.,
2H, −CH ₂ −O−), 4.27(dd1H, −CH −CH ₂ O
-), 7.12-7.43 (m, 5H, Ph), 7.74 (q., 1H, -
CH=N-) Example 6 (-)-2-{(2S)-2-[(1R)-2-methoxy-1-phenylethyl]aminopropyl}-4,
4-Dimethyl-2-oxazoline In Example 2, (-)-( R)-
Using 7.15 mmol of N-ethylidene-2-methoxy-1-phenylethylamine at -65 to -60°C, 6.5
The reaction conditions were changed to −80° C. for 4.5 hours to give the title compound as an oil. Yield; 96% [α] ¹⁹ _D −77.4° (C = 2.97, hexane) IR (film); 1660, 3320 cm ⁻¹ NMR (CDCl ₃ ) δ ^TMS _ppn ; 1.02 (d., 3H, C H ₃ − CH
-N-), 1.24 (s., 6H), 2.36 (oct., 2H), 2.74~
3.06 (m., 1H, [formula]), 3.32 (s., OCH ₃ ), 3.36 (d., −CH ₂ O−, repeating, 5H), 3.85 (s., 2H),
4.10 (dd, 1H, [formula]), 7.14-7.43 (m., 5H, Ph) Example 7 (-)-(3S)-3-[(1R)-2-methoxy-1
-Phenylethyl]aminobutyric acid In Example 3, (-)-2-{(2S)-2-
[(1R)-2-methoxy-1-phenylethyl]amino-4-methylpentyl}-4,4-dimethyl-2-oxazoline instead of (-)-2-{(2S)
-2-[(1R)-2-methoxy-1-phenylethyl]aminopropyl}-4,4-dimethyl-2-
Using oxazoline, the hydrochloride salt of the title compound was obtained in the form of a hygroscopic amorphous powder. Yield 93% [α] ¹⁹ _D −26.7° (C = 3.30, water) NMR (CDCl ₃ ) δ ^TMS _ppn ; 1.43 (d., 3H, CH ₃ −CH
-N-), 2.50-3.07 (m., 2H, _-CH2COOH ),
3.44 (s., OCH ₃ and 3.29-3.58 (m., CH ₃ −CH
-N) (repeat, 4H), 3.61~3.86 (m., 1H, -
CH ₂ OCH ₃ ), 4.07-4.58 (m., 2H, repeating,
[Formula] 7.32-7.58 (m., 3H, 3,4,5-prototon of Ph), 7.58-7.85 (d.,
(2,6-proton of 2H, Ph) The above compound was ion-exchanged using an ion-exchange resin IR-120 (elution solvent: 1.5N aqueous ammonia) to obtain an oily free acid. Yield 96% [α] ¹⁹ _D −25.1° (C = 3.03, water) NMR (D ₂ O) δ ^DSS _ppn ; 1.23 (d., 3H, −N−CH・
CH ₃ ), 2.46 (oct., 2H, − CH ₃ −COOH), 3.43
(s., OCH ₃ ) and 3.26-3.56 (m.,
[Formula]) (repeat, 3H), 3.79 (oct., 2H, -O CH ₃ CH), 4.58 (dd, 1H, -OCH ₂
[Formula]), 7.45 (s., 5H, Ph) 7.45 (s., 5H, Ph) Mass (EI) m/z; 238 (MH ⁺ ), 237 (M ⁺ ) Example 8 (+) - ( S)-3-aminobutyric acid In Example 4, (-)-(3S)-3-[(IR)-
2-methoxy-1-phenylethyl]amino-5
-Instead of methylhexanoic acid/hydrochloride (-)-
(3S)-3-[(IR)-2-methoxy-1-phenylethyl]aminobutyric acid hydrochloride (+)-
(S)-3-aminobutyric acid was obtained. Yield 88% Melting point; 209-209.5°C (decomposition) [α] ²¹ _D −36.5° (C = 1.04, water) NMR (D ₂ O) δ ^DSS _ppn ; 1.31 (d., 3H, -CH-
_CH3 ), 2.46 (d., 2H, _−CH2COOH ), 3.37-3.79
(m., 1H, [formula]) Mass (EI) m/z; 104 (MH ⁺ ), 103 (M ⁺ ) The melting point of the recrystallized product from methanol is 211.5-212
°C (decomposition) and [α] ²¹ _D +37.9° (C = 1.04, water)
has. The value in the literature [J.Chem.Soc., 1952 , 3316] is melting point: 212℃, [α] ¹⁸ _D + 38.8℃ (C = 0.48, water), so the above product has extremely high optical purity. It turns out that it is something. Example 9 (-)-(R)-N-butylidene-2-methoxy1-phenylethylamine In Example 1, butyraldehyde was used instead of isovalerylaldehyde to quantitatively produce (-)-(R). )-N-butylidene-2-methoxy-1
-Phenylethylamine was obtained. [α] ²⁴ _D −40.9° (C=4.42, hexane) IR (film); 1665, cm ^-1 NMR (CDCl ₃ ) δ ^TMS _ppn ; 0.93 (t., 3H, − CH _2
CH3 ), 1.33-1.81 (m., 2H, _{-CH2 , CH2CH3} ),
2.13-2.43 (m., 2H, −N=CH CH ₂ −), 3.32 (s.,
3H, _-OCH3 ), 3.61(d.,2H, _{-CH2CH2 -} O-),
4.26 (t., 1H, [formula]), 7.15-7.42 (m., 5H, Ph), 7.68 (t., 1H, - CH = N-) Example 10 (-) -2- {(2S) -2-[(1R)-2-methoxy-1-phenylethyl]aminobutyl}-4,
4-Dimethyl-2-oxazoline In Example 2, (-)-(R)- in place of (-)-(R)-N-(3-methylbutylidene)-2-methoxy-1-phenylethylamine -78°C instead of 6.5 hours at -65 to -60°C using N-butylidene-2-methoxy-1-phenylethylamine.
The reaction was carried out for 8 hours to obtain the title compound as an oil. Yield 88%. IR (film); 1665 cm ^-1 NMR (CDCl ₃ ) δ ^TMS _ppn ; 0.77 (t., 3H, −CH _2
CH3 ), 1.24 (s., 4,4-dimethyl of oxazoline) and 1.10-1.55 (m., _-CH2
[Formula] (repeated, 10H), 2.38 (d., 2H, _-CH2 -oxozoline), 2.57-2.86 (m.,
[Formula] oxazoline), 3.32 (s., -OCH ₃ ) and 3.36 (d., [Formula]) (duplicate, 5H) Example 11 (-)-(3S)-3-[(1R)-2- Methoxy-1
-Phenylethyl]aminohexanoic acid In Example 3, (-)-2-{(2S)-2-
[(IR)-2-methoxy-1-phenylethyl]amino-4-methylpentyl}-4,4-dimethyl-2-oxazoline instead of (-)-2-{(2S)
-2-[(IR)-2-methoxy-1-phenylethyl]aminobutyl}-4,4-dimethyl-2-oxazoline was used to obtain the hydrochloride salt of the title compound in the form of an amorphous powder. Yield 80% NMR (D ₂ O) δ ^DSS _ppn ; 1.76 (t., 3H, CH ₃ -CH ₂
−), 1.03 to 1.46 (m., 2H, CH ₃ CH ₂ −), 1.50 to
1.83 (m., 2H, [formula]), 2.76 (oct., 2H, −CH ₂ COOH), 3.43 (s., OCH ₃ ) and 3.30
~3.58 (m., [formula]) (repeat, 3H), 3.88 (oct., 2H, − CH ₂ OCH ₃ ), 7.46 (s.,
5H, Ph) The above compound was ion-exchanged using an ion-exchange resin IR-120 (elution solvent: 1.5N aqueous ammonia) to obtain an oily free acid. Yield 93% NMR (D ₂ O) δ ^DSS _ppn ; 0.73 (t., 3H, −CH ₂ CH ₃ ,
1.02-1.73 (m., 4H, − CH ₂ CH ₂ CH ₃ ), 2.46 (oct.,
2H, −CH ₂ COOH), 3.11 to 3.37 (m., 1H,
[Formula]), 3.43 (s., 3H, OCH ₃ ), 3.87 (oct., 2H, −CH ₂ OCH ₃ ), 7.46 (s., 5H,
Ph) Mass (EI) m/z; 266 (MH ⁺ ) Example 12 (+)-(S)-3-aminohexanoic acid In Example 4, (-)-(3S)-3-[(IR) −
2-methoxy-1-phenylethyl]amino-5
-Instead of methylhexanoic acid/hydrochloride (-)-
(+)-(S)-3-aminohexanoic acid was obtained using (3S)-3-[(IR)-2-methoxy-1-phenylethyl]aminohexanoic acid and hydrochloride. yield
89% Melting point; 199.5-200°C (decomposition) [α] ²³ _D +34.9° (C = 8.46, water) NMR (D ₂ O) δ ^DSS _ppn ; 0.90 (t., 3H, CH ₃ CH ₂ CH ₂
−, 1.14 to 1.76 (m., 4H, CH ₃ CH ₂ CH ₂ −), 2.39
(oct., 2H, − CH ₂ COOH), 3.30~3.62 (m., 1H,
[Formula]) The recrystallized product from methanol-diethyl ether has a melting point of 204-205℃ (decomposition) and [α] ²¹ _D +
3.65 (C=2.19, water). Literature [Ber., 66 ,
591 (1933)] Value is melting point; 205-207℃, [α] ¹⁷ _D +
35.6 (C=8.40, water), it was found that the above product had extremely high optical purity. Example 13 (-)-(R)-N-cyclohexylmethylene-
2-methoxy-1-phenylethylamine (-)
3.02 g (20 mmol) of -(R)-2-methoxy-1-phenylethylamine was dissolved in 50 ml of dry benzene, and 20 mmol of cyclohexanaldehyde and 12.05 g (100 mmol) of anhydrous magnesium sulfate were added to the solution while stirring under ice-cooling and a nitrogen gas stream. mol) and stirred for 6-10 hours. During this time, the temperature was gradually returned to room temperature. After the reaction, magnesium sulfate was removed and concentrated under reduced pressure to obtain oily (-)-(R)-cyclohexylmethylene-
2-methoxy-1-phenylethylamine was obtained quantitatively. [α] ²⁰ _D −26.6° (C=2.22, hexane) IR (film); 1670 cm ^-1 NMR (CDCl ₃ ) δ ^TMS _ppn ; 1.00 to 2.50 (m, 11H,
[Formula]), 3.34 (s., 3H, OCH ₃ ), 3.61 (d., 2H, −CH ₂ OCH ₃ ), 4.26 (t., 1H, =N−CH
H), 7.16-7.52 (m., 5, Ph), 7.59 (d., 1H,
-C H = N-) Example 14 (-)-(R)-N-benzylidene-2-methoxy-1-phenylethylamine In Example 13, quantitative oily The title compound was obtained. [α] ²⁰ _D +66.5° (C=3.23, hexane) IR (film); 1650 cm ^-1 NMR (CDCl ₃ ) δ ^TMS _ppn ; 3.30 (s., 3H, −OCH ₃ ),
3.69 (d., 2H, -C H ₂ OCH ₃ ), 4.49 (t., 1H, = N
-CH- ), 7.1-7.8 (m., 10H, Ph x 2), 8.27
(s., 1H, -CH=N-) Example 15 (-)-2-{(2S)-2-[(1R)-2-methoxy-1-phenylethyl]amino-2-cyclohexylethyl}-4 ,4-dimethyl-2-oxazoline In Example 2, (-)-(R)-N-(3-methylbutylidene)-2-methoxy-1-phenylethylamine was replaced by (-)-(R) -N-Cyclohexylmethylene-2-methoxy-1-phenylethylamine was used to obtain the title compound in the form of an oil. Yield 96%. [α] ²⁰ _D −61.6° (C=0.97, hexane) IR (film); 1662 cm ^-1 NMR (CDCl ₃ ) δ ^TMS _ppn ; 0.6 to 2.20 (m., 11H,
[Formula]) 1.25-1.26 (each s., 6H, [Formula]), 2.43 (m., 2H, - CH ₂ - oxazoline ring), 2.36-2.64 (m., 1H,
[Formula]) 3.33 (s., 3H, −OCH ₃ ), 3.37 (d., 2H, −CH ₂ OCH ₃ ), 3.88 (s., 2H,
[Formula]) 4.30 (t., 1H, -CH-Ph), 7.12 to 7.60 (m., 5H, Ph) Example 16 (-)-2-{(2S)-2-[(1R)-2 -methoxy-1-phenylethyl]amino-2-phenylethyl}-4,4-dimethyl-2-oxazoline In Example 2, (-)-(R)-N-(3-methylbutylidene)-2-methoxy- Using (-)-(R)-N-benzylidene-2-methoxy-1-phenylethylamine in place of 1-phenylethylamine, the title compound as an oil was quantitatively obtained. [α] ²⁰ _D −12.8° (C=4.28, hexane) IR (film); 1670 cm ^-1 NMR (CDCl ₃ ) δ ^TMS _ppn ; 1.10, 1.18 (each s., 6H,
[Formula]) 2.64 (oct., 2H-C H ₂ -oxazoline), 3.33 (s., 3H-OCH ₃ ), 3.48 (d., 2H, -C
H ₂ OCH ₃ ), 3.80 (s., 2H, [formula]), 3.90 (dd, 1H, PhCH), 4.08 (t., 1H,
[Formula]), 7.1 to 7.3 (m., 10H, Ph×2) Example 17 In Example 3, (-)-2-{(2S)-2-
Example 15 and [(IR)-2-methoxy-1-phenylethyl]amino-4-methylpentyl}-4,4-dimethyl-2-oxazoline, respectively.
Using the oxazoline compound obtained in step 16, the following compound was obtained. (-)-(3S)-3-[(IR)-2-methoxy-1
-Phenylethyl]amino-3-cyclohexylpropionic acid hydrochloride, amorphous powder Yield: 36% [α] ²⁰ _D -12.1° (C=0.66, water) NMR (D ₂ O) δ ^DSS _ppn : 0.6 to 2.0 (m., 11H,
[Formula]) 2.79 (oct., 2H, -CH ₂ COOH), 3.24-3.52 (m., 1H, [Formula]), 3.46 (s., 3H, -OCH ₃ ), 3.68-4.20 (m. ,2H,−
CH ₂ OCH ₃ ), 4.70 (dd, 1H, −CH−Ph), 7.45
(s.,5H,Ph)(-)-(3S)-3-[(IR)-2-methoxy-1-phenylethyl]amino-3-phenylpropionic acid hydrochloride, amorphous powder Yield: 82 % [α] ²⁰ _D −16.6° (C=2.56, water) NMR (D ₂ O) δ ^DSS _ppn ; 3.20 (oct., 2H, −
CH ₂ COOH), 3.45 (s., 3H, −OCH ₃ ), 3.8-4.1
(m., 2H, -CH ₂ OCH ₃ ), 4.53 (dd, 1H, -CH
CH ₂ COOH), 4.74 (dd, 1H, Ph-C H -), 7.2
~7.5 (m., 10H, Ph x 2) Example 18 (+)-(S)-3-amino-3-cyclohexylpropionic acid In Example 4, (-)-(3S)-3-[(IR )−
2-methoxy-1-phenylethyl]amino-5
-Instead of methylhexanoic acid/hydrochloride (-)-
(3S)-3-[(IR)-2-methoxy-1-phenylethyl]amino-3-cyclohexylpropionic acid hydrochloride to form crystalline (+)-(S)-3-
Amino-3-cyclohexylpropionic acid was obtained. Yield 70% Melting point; 238-239°C [α] _D +35.8° (C = 1.0, water) NMR (D ₂ O) δ ^DSS _ppn ; 0.6-2.0 (m., 11H,
[Formula]), 2.49 (oct., 2H-CH ₂ COOH), 3.16-3.52 (m., 1H, - CH CH ₂ COOH) Example 19 (+)-(S)-3-amino-3- Phenylpropionic acid (-)-(3S)-3-[(IR)-2-methoxy-1
-Phenylethyl]Amino-3-phenylpropionic acid hydrochloride 200 mg (0.60 mmol) was dissolved in 10 ml of 50% aqueous ethanol, and 10% Pd/C200 was added to this.
mg and hydrogenated for 2 days at room temperature with vigorous stirring. After the reaction, the catalyst was removed and the mother liquor was concentrated under reduced pressure. The residue was purified by flash chromatography [silica gel 60 Merck Art 9385, developing solvent chloroform-methanol (1:1)] to obtain 30 mg of the hydrochloride of the title compound. Dowex this
(50W x 2100-200 meshes) to obtain the free acid. Melting point: 238-240℃ [α] _D +7.1° (C=0.8, water) NMR (D ₂ O) δ ^DSS _ppn : 2.86 (d.ABq.2H, CH ₂ ),
4.64 (t., 1H, CH), 7.47 (s., 5H, Ph) Literature value 1 [Ber., 43 , 2070 (1910)] Melting point; 234-235℃, [α] _D + 6.9° (water ) Literature value 2 [J.Am Chem.Soc., 86 , 725 (1964)] Melting point: 232-233℃, [α] _D +10.6° (C=65, water) Reference example 4 (+) - ( S)-2-Methoxy-1-phenylethylamine In Reference Examples 1 and 2, (+)- in place of (-)-(R)-2-amino-2-phenylethanol
(+)-(S)-2-methoxy-1-phenylethylamine was obtained using (S)-2-amino-2-phenylethanol. [α] _D +48.05° (C=4.61, benzene) Boiling point: 79-81°C/4 mmHg NMR (CDCl ₃ ): Exactly the same as the title compound of Reference Example 3. Example 20 (+)-(S)-N-(3-methylbutylidene)-2-methoxy-1-phenylethylamine (+)-(S)-2-methoxy-1-phenylethylamine 3.02 g ( 20mmol) of dry benzene 50ml
20 mmol of isovaleraldehyde and 12.05 g (5 times the mole) of anhydrous magnesium sulfate were added thereto under ice-cooling and stirring under a nitrogen gas stream, and the mixture was stirred at room temperature for 6 to 10 hours. After the reaction, the dehydrating agent was removed, and the benzene was distilled off under reduced pressure at 40°C or lower to obtain an oily (+)-(S)-N-(3-methylbutylidene)-2-.
Methoxy-1-phenylethylamine was obtained quantitatively. [α] ²⁰ _D +30.7° (C=2.73, hexane) NMR (CDCl ₂ ); Exactly the same as the title compound of Example 1. Example 21 (+)-2-{(2R)-2-[(1S)-2-methoxy-1-phenylethyl]amino-4-methylpentyl}-4,4-dimethyl-2-oxazoline 2,4, 4-trimethyl-2-oxazoline
1.0 ml (0.89 g) dry tetrahydrofuran (25
ml) 5.0 ml of a 1.55 M butyllithium/hexane solution was added dropwise to the solution through a syringe over 15 minutes while stirring and cooling to -70 to -75°C under a stream of dry nitrogen gas.
Stir for 30 minutes. To this (+)-(S)-N-(3-
A solution of 7.15 mmol of methylbutylidene)-2-methoxy-1-phenylethylamine in dry tetrahydrofuran (15 ml) was added over 30 minutes at -65 to -60°C.
Stirred for 6.5 hours. The reaction solution was poured into a mixture of saturated ammonium chloride aqueous solution and diethyl ether, and extracted. The aqueous layer was extracted three times with diethyl ether, combined with the previous ether layer, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound as an oil. Yield 95%. [α] _D +89.6° (C=3.52, hexane) IR (film), 1675 cm ⁻¹ NMR (CDCl ₃ ); Exactly the same as the title compound of Example 5. Example 22 (+)-2-{(2R)-2-[(1S)-2-methoxy-1-phenylethyl]amino-2-cyclohexylethyl-4,4-dimethyl-2-oxazoline In Example 21, (+)-(S)-N-cyclohexylmethylene-2-methoxy-1-phenylene instead of (+)-(S)-N-(3-methylbutylidene)-2-methoxy-1-phenylethylamine. Enylethylamine was used to obtain the title compound as an oil.
Yield 90%. [α] _D +60.0° (C=0.96, hexane) IR (film), 1665 cm ⁻¹ NMR (CDCl ₃ ); Exactly the same as the title compound of Example 15. Example 23 (+)-2-{(2R)-2-[(1S)-2-methoxy-1-phenylethyl]amino-2-phenylethyl}-4,4-dimethyl-2-oxazoline In Example 21, (+)-(S)-N-benzylidene-2-methoxy-1-phenyl instead of (+)-(S)-N-(3-methylbutylidene)-2-methoxy-1-phenylethylamine Ethylamine was used to obtain the title compound as an oil. Yield 98%. [α] _D +13.9° (C=23.7, hexane) IR (film); 1670 cm ⁻¹ NMR (CDCl ₃ ); Exactly the same as the title compound of Example 16. Example 24 In Example 3, (-)-2-{(2S)-2-
Using the oxazoline compounds obtained in Examples 21, 22 and 23 in place of [(1R)-2-methoxy-1-phenylethyl]amino-4-methylpentyl}-4,4-dimethyl-2-oxazoline, respectively, The following compound was obtained. (+)-(3R)-3-([(1S)-2-methoxy-1
-Phenylethyl]amino-5-methylhexanoic acid, hydrochloride, amorphous powder. Yield 80%. [α] _D +26.7° (C=1.41, water) NMR (D ₂ O): Exactly the same as the hydrochloride of the title compound obtained in Example 3. (+)-(3R)-3-[(1S)-2-methoxy-1
-Phenylethyl]amino-3-cyclohexylpropionic acid hydrochloride. Amorphous powder. Yield: 78%. [α] _D +10.2° (C=1.03, water) NMR (D ₂ O); (-)-(3S)- obtained in Example 17
3-[(1R)-2-methoxy-1-phenylethyl]amino-3-cyclohexylpropionic acid.
Exactly the same as hydrochloride. (+)-(3R)-3-[(1S)-2-methoxy-1
-Phenylethyl]amino-3-phenylpropionic acid hydrochloride. Amorphous powder. Yield: 91%. [α] _D +15.6° (C = 2.04 water) NMR (D ₂ O); (-)-(3S)- obtained in Example 17
It is exactly the same as 3-[(1R)-2-methoxy-1-phenylethyl]amino-3-phenylpropionic acid hydrochloride. Example 25 (-)-(R)-3-amino-5-methylhexanoic acid In Example 4, (-)-(3S)-3-[(1R)-
2-methoxy-1-phenylethyl]amino-5
-Instead of methylhexanoic acid/hydrochloride (+)-
The title compound was obtained using (3R)-3-[(1S)-2-methoxy-1-phenylethyl]amino-5-methylhexanoic acid hydrochloride. Crystal form. Yield: 77%. Melting point: 238-239°C (decomposition) [α] _D −29.8° (C = 1.0, water) NMR (D ₂ O): (+)-(S)- obtained in Example 7
It is exactly the same as 3-amino-5-methylhexanoic acid. Example 26 (-)-(R)-3-amino-3-cyclohexylpropionic acid In Example 4, (-)-(3S)-3-[(1R)-
2-methoxy-1-phenylethyl]amino-5
-Instead of methylhexanoic acid/hydrochloride (+)-
Using (3R)-3-[(1S)-2-methoxy-1-phenylethyl]amino-3-cyclohexylpropionic acid hydrochloride, the title compound in crystalline form was obtained. Yield: 87%. Melting point: 240-241°C (decomposition) [α] _D −35.8° (C = 1.0, water) NMR (D ₂ O): (+)-(S)- obtained in Example 18
It is exactly the same as 3-amino-3-cyclohexylpropionic acid. Example 27 (-)-(R)-3-amino-3-phenylpropionic acid In Example 19, (-)-(3S)-3-[(1R)-
2-methoxy-1-phenylethyl]amino-3
-Instead of phenylpropionic acid/hydrochloride (+)
-(3R)-3-[(1S)-2-methoxy-1-phenylethyl]amino-3-phenylpropionic acid.
The title compound in crystalline form was obtained using the hydrochloride. Melting point: 238-240°C (decomposition) [α] _D −7.4° (C = 0.9, water) NMR (D ₂ O): (+)-(S)- obtained in Example 19
It is exactly the same as 3-amino-3-phenylpropionic acid. Literature values [Ber., 43 , 2070 (1910)] Melting point: 234-235°C (decomposition) [α] 7.5° (water).

Claims (1)

[Claims] 1 formula (In the formula, R is a lower alkyl, phenyl or cycloalkyl group, Ph is a phenyl group, and * means an optically active asymmetric carbon atom). 1. A method for producing an optically active β-amino acid, the method comprising: 2 formulas (In the formula, R is a lower alkyl, phenyl or cycloalkyl group, Ph is a phenyl group which may have a substituent, and *C means an optically active asymmetric carbon atom) The formula obtained by acid hydrolysis is (In the formula, R and Ph mean the same groups as above,
A method for producing an optically active β-amino acid, which comprises removing α-methoxymethyl-benzylation of a compound represented by *C has the same meaning as above) by reduction. 3 (wherein, R is a lower alkyl, phenyl or cycloalkyl group, Ph is a phenyl group, and *C is an optically active asymmetric carbon atom). By reacting with a lithiooxazoline compound represented by the formula (In the formula, and Ph mean the same group as above, *
C has the same meaning as above), acid hydrolyzed the compound, and the resulting formula (In the formula, R and Ph mean the same groups as above,
A method for producing an optically active β-amino acid, which comprises removing α-methoxymethyl-benzylation of a compound represented by *C has the same meaning as above) by reduction.