JP2000072728A - Production of optically active alpha-substituted-beta- aminoketone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To directly produce an optically active α-substituted-β-aminoketone derivative from an optically inactive starting raw material by carrying out asymmetric Mannich reaction using a specific comples, a Lewis acid and a specific derivative. SOLUTION: (A) A synthetic zeolite, (B) a ketone and (C) an optically active aluminum-alkali metal-binaphthol complex of formula I, etc., are stirred and mixed in a solvent under an inert gas atmosphere and the mixture is reacted with (D) a Lewis acid of formula II (M is lanthanum, ytterbium or scandium; (m) is a positive number) and an α-aminoether derivative of formula III [R1 is a lower alkyl, phenyl or benzyl; R2 and R3 are each an (un)saturated lower alkyl or the like] to obtain the objective derivative of formula IV [R4 is a group of formula V (R7 is trifluoromethyl or a lower alkyl) or the like] having asymmetric structure induced at the α-position of the component B. The derivative has central muscle relaxing action.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active α-substituted-β-aminoketone derivative having a central muscle relaxing action, and to asymmetric catalytic synthesis of this derivative using a multifunctional complex metal complex. And a method for producing the same.

[0002]

2. Description of the Related Art Optically active α- having a central muscle relaxing action
As a method for producing a substituted-β-aminoketone derivative, a racemic optical resolution method is known. For example, JP-A-1-13
No. 1171 discloses an optically active 2-methyl-methyl ester using acetylphenylglycine or malic acid as an optical resolving agent.
A method for producing 1- (4-trifluoromethylphenyl) -5-pyrrolidino-1-propanone is disclosed. Japanese Patent Application Laid-Open No. 8-208572 discloses an optically active 3-phenyl wherein after using camphorsulfonic acid as an optical resolving agent, a desired optical isomer is obtained and the unnecessary isomer is recovered by racemization. A method for producing -5- {2- (pyrrolidinylmethyl) butyryl} isoxazole is shown.

However, in these methods, a desired optical isomer is obtained and an unnecessary optical isomer is simultaneously produced in an equal amount. However, it is not always an excellent method. In the example of Japanese Patent Application Laid-Open No. 8-208572, the above-mentioned problem is solved by recovering unnecessary optical isomers by racemization. However, the production process is increased by adding a recovery step. Therefore, it is difficult to say that the method is still sufficiently excellent, and it has been desired to develop a catalytic asymmetric synthesis method.

[0004]

The object of the present invention is to use an optically active aluminum-alkali metal-binaphthol complex, which is a multifunctional complex metal complex, as a catalyst without using the above-mentioned optical resolution method, and at the same time to use Lewis acid. An object of the present invention is to provide a method for directly producing an optically active α-substituted-β-aminoketone derivative from an optically inactive starting material by coexistence and an asymmetric Mannich reaction using an α-aminoether derivative.

[0005]

Means for Solving the Problems The present inventors have developed a multifunctional complex metal complex containing an optically active aluminum-alkali metal-binaphthol complex and the like, and used this as a catalyst.
Asymmetric aldol reaction, asymmetric hydrophosphonylation reaction,
It has been reported usefulness in asymmetric Diels-Alder reaction, asymmetric Michael reaction, etc. (Angevante Chemie
International Edition in English, Vol. 36, p. 1236, 1997). The above-mentioned α-substituted-β-aminoketone derivatives can be generally produced by a Mannich reaction using ketones, formaldehydes and secondary amines as starting materials. The addition of a catalytic amount of an optically active aluminum-alkali metal-binaphthol complex and a Lewis acid to the reaction system to produce an optically active α-substituted-β-aminoketone derivative in which asymmetry is induced at the α-position of ketones. And completed the present invention.

That is, the present invention provides an asymmetric Mannich reaction using an optically active aluminum-alkali metal-binaphthol complex, a Lewis acid and an α-aminoether derivative.
A method for producing an optically active α-substituted-β-aminoketone derivative, wherein the optically active aluminum-alkali metal-binaphthol complex is represented by the general formula (1) [General formula (1-1)
And (1-2)]

Embedded image A method for producing an optically active α-substituted-β-aminoketone derivative, which is a compound represented by

The Lewis acid has the general formula (2)

Embedded image Wherein M represents a lanthanum atom, a ytterbium atom or a scandium atom, and m represents a positive number, and is a method for producing an optically active α-substituted-β-aminoketone derivative,

Further, the α-amino ether derivative has the general formula (3)

Embedded image [Wherein, R1 represents a lower alkyl group, a phenyl group or a benzyl group, R2 and R3 independently represent a saturated or unsaturated lower alkyl group, or R2 and R3 become one to form a general formula (4)

Embedded image (In the formula, n represents 0 or an integer of 1 to 2, and Z represents an oxygen atom, a methylene group, an amino group, a methylamino group, or a benzylamino group.) A method for producing an optically active α-substituted-β-aminoketone derivative

The optically active α-substituted-β-aminoketone derivative has the general formula (5)

Embedded image [In the formula, R4 is the general formula (6) [the general formulas (6-1) and (6-2)]

Embedded image (R6 is a halogen atom; a lower alkyl group; a benzyl group;
Benzoyl group; pyridyl group; furyl group optionally substituted by lower alkyl group; thienyl group optionally substituted by lower alkyl group; halogen atom, lower alkoxy group, trifluoromethyl group, cyano group, nitro group, amino group A phenyl group which may be substituted with a dimethylamino group, an acetamido group, a methanesulfonylamido group, an acetyl group or a lower alkoxycarbonyl group; or a naphthyl group; R7 represents a trifluoromethyl group or a lower alkyl group;
Y represents an oxygen atom or a sulfur atom), and R2 is a lower alkyl group; a benzyl group; a methoxy group; a phenyl group; an allyl group; an alkyl group substituted with a trifluoromethyl group or a lower alkoxy group; R3 and R4 each independently represent a saturated or unsaturated lower alkyl group, and R3 and R4 become one to form a general formula (4)

Embedded image (In the formula, n represents 0 or an integer of 1 to 2, and Z represents an oxygen atom, a methylene group, an amino group, a methylamino group, or a benzylamino group.) Optical activity α represented by｝
A method for producing a substituted-β-aminoketone derivative.

The specific embodiments of the present invention are as follows. That is, under an inert gas atmosphere such as argon and nitrogen, as a reaction solvent, petroleum ether, n-hexane, peptane, aliphatic hydrocarbons such as cyclohexane, benzene, toluene, aromatic hydrocarbons such as xylene, dichloromethane, Halogen such as chloroform and carbon tetrachloride,
Using an ester solvent such as ethyl acetate-n-butyl acetate, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, an ether solvent such as diglyme and a mixed solvent of two or more thereof, synthetic zeolite,

The general formula (7) [General formulas (7-1) and (7)
-2)]

Embedded image (Wherein R2, R5, R6 and Y are the same as described above), and a general formula (1) [general formula (1-1)
And (1-2)]:

Embedded image (Wherein X is the same as described above), and mixed and stirred with an optically active aluminum-alkali metal-binaphthol complex represented by the following formula:

General formula (3)

Embedded image (Wherein R1, R2 and R3 are the same as described above) represented by the general formula (2):

Embedded image (In the formula, M represents a lanthanum atom, a ytterbium atom, or a scandium atom, and m represents a positive number.) A Lewis acid, which is a compound represented by the formula, is added, and the mixture is stirred and reacted.

The course of the reaction is determined by thin-layer chromatography,
It can be easily tracked and confirmed by analytical means such as gas chromatography and high performance liquid chromatography. Post-treatment after completion of the reaction is performed as follows. The synthetic zeolite is removed by filtration from the reaction suspension, and is dissolved in an acidic aqueous solution such as dilute hydrochloric acid, and then washed with an organic solvent immiscible with water. Thereafter, the aqueous layer containing the target substance is neutralized with an aqueous ammonia solution or the like, extracted with a water-immiscible organic solvent, and after removing water with a dehydrating agent such as magnesium sulfate and sodium sulfate,
The crude product obtained by distilling off the solvent under reduced pressure is crystallized, distilled under reduced pressure, and column chromatography (as the adsorbent,
Commercially available silica gel, alumina, florisil and the like can be used. ) To obtain the desired product.

It is also effective to form a salt of the crude product using a mineral acid such as hydrochloric acid or sulfuric acid or a sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid and to isolate and purify the crystal as a crystal. . The amount of the reaction solvent used is not particularly limited, but is preferably 0 to 100 times the weight of the ketone represented by the general formula (7). More preferably, the amount is 1 to 20 times by weight.

As the synthetic zeolite, commercially available molecular sieves 3A, molecular sieves 4A, molecular sieves 5A, molecular sieves 10X, molecular sieves 15X and the like can be used, and among them, the molecular sieve 3A is preferable. The amount used is not particularly limited, but is usually 5 to 100 times the weight of the ketone represented by the general formula (7).
More preferably, the amount is 10 to 20 times by weight.

The amount of the optically active aluminum-alkali metal-binaphthol complex represented by the general formula (1) is 0.01 to 0.01 with respect to the ketone represented by the general formula (7).
A 0.2 molar amount is possible, but preferably 0.05 to
It is 0.1 mole times. The amount of the Lewis acid represented by the general formula (2) can be 0.01 to 0.2 times the mol of the ketones represented by the general formula (7), but is preferably 0. It is 0.05 to 0.1 times by mole. The α-aminoether derivative represented by the general formula (3) is disclosed in Journal of American Chemical Society, Vol.
It can be prepared by the method described in the literature such as 4172 pages, 1932 and the like, and its use amount can be 1 to 10 times the molar amount of the ketone represented by the general formula (7).
２2 molar times. The reaction temperature can be from −78 ° C. to the boiling point of the solvent used, but is preferably −78 ° C. to + 50 ° C. from the viewpoint of the reaction yield and the optical purity. More preferably, the temperature range is from -40C to + 25C.

[0017]

EXAMPLES Next, the present invention will be described more specifically based on examples, but the present invention is not limited to these examples. Optical Purity The optical purity in the examples can be measured by high-performance liquid column chromatography analysis of a normal layer system or a reverse layer system, and is represented by the enantiomeric excess (% ee) of the formula 1. (Formula 1): enantiomeric excess = {(peak area of target) − (peak area of enantiomer)} × 100 {(peak area of target) +
(Peak area of antipod)｝

Reference Example 1 Preparation of aluminum-lithium- (R) -binaphthol complex [general formula (1-1)] (hereinafter abbreviated as (R) -ALB) 1.8 lithium aluminum hydride in an argon atmosphere
98 g (50 mmol) of tetrahydrofuran 200 m
and (R)-(+)-1,1′-bi- at 0 ° C.
28.64 g (100 mmol) of 2-naphthol / 300 ml of tetrahydrofuran were added dropwise over 30 minutes. 0
After stirring at 30 ° C. for 30 minutes, the mixture was stirred at room temperature for 1 hour, and allowed to stand at room temperature overnight, and the supernatant was used as a 0.1 M (R) -ALB tetrahydrofuran solution.

Reference Example 2 Preparation of aluminum-lithium- (S) -binaphthol complex [general formula (1-2)] (hereinafter abbreviated as (S) -ALB) In the operation of Reference Example 1, (R)-( +)-1,1'-
Bi-2-naphthol instead of (S)-(-)-1,
Prepared using 1'-bi-2-naphthol, 0.1M
(S) -ALB was used as a tetrahydrofuran solution.

Example 1 Synthesis of (R) -2-methyl-1-phenyl-3-diethylamino-1-propanone (Compound No. 1)

Embedded image Molecular sieves 3A11.1 under argon atmosphere
g, lanthanoid triflate [La (OTf) _3.
nH2O (n = 8-9)] 0.54 g, and 0.07 g
4M (R) -ALB solution in tetrahydrofuran 10ml
And tetrahydrofuran was distilled off under reduced pressure. Toluene (35 ml) was added, and diethylaminomethyl methyl ether (1.07 ml, 7.4 mmol) was added. Further, 0.98 ml (7.4 mmol) of propiophenone was added, and the mixture was stirred at room temperature for 36 hours.

From the reaction suspension, molecular sieves were removed by filtration, extracted with 30 ml of 5N hydrochloric acid three times, and the aqueous layer was washed with diethyl ether (10 ml × 2). The aqueous layer was neutralized with 400 ml of a 5% aqueous ammonia solution while cooling, and extracted with diethyl ether (100 ml × 3). The organic layer
After washing with 100 ml of saturated saline, anhydrous sodium sulfate 1
Dried at 0 g. The solvent was distilled off under reduced pressure to obtain 0.86 g (3.9 mmol) of the title compound (yield 53%).

1H-NMR (C ₆ D ₆ , 500 MHz): δ 0.90 (6H, t, J = 7.0 Hz), 1.17
(3H, d, J = 6.7 Hz), 2.37 (4H, q,
J = 7.0 Hz), 2.39 (1H, dd, J = 6.
4,12.8 Hz), 2.94 (1H, dd, J = 5.
2,12.8 Hz), 3.52-3.59 (1H,
m,), 7.08-8.00 (5H, m). Enantiomeric excess: 30% ee

Example 2 Synthesis of (R) -2-methyl-1- (4-trifluoromethylphenyl) -3-pyrrolidino-1-propanone hydrochloride (Compound No. 2)

Embedded image 16.65 g of molecular sieves 3A under a nitrogen atmosphere
Lanthanoid triflate [La (OTf) ₃ · n
H2O (n = 8-9)], 0.81 g, and 0.1M
11 ml of a tetrahydrofuran solution of (R) -ALB was added, and tetrahydrofuran was distilled off under reduced pressure. 50 ml of benzene was added, and 1.28 g (11.1 mmol) of pyrrolidinomethyl methyl ether was added. Further 1-
(4-trifluoromethylphenyl) -propanone
24 g (11.1 mmol) was added, and the mixture was stirred at room temperature for 48 hours. The molecular sieves were filtered off from the reaction suspension, extracted with 45 ml of 5N hydrochloric acid three times, and the aqueous layer was washed with diethyl ether (15 ml × 2). The aqueous layer was neutralized with 600 ml of a 5% aqueous ammonia solution while cooling, and extracted with diethyl ether (150 ml × 3). The organic layer
After washing with 150 ml of saturated saline, anhydrous sodium sulfate 1
Dry with 5 g. 4N hydrochloric acid / dioxane solution 10 under ice-cooling
Then, the mixture was stirred at room temperature for 1 hour. The crystals obtained by evaporating the solvent under reduced pressure were washed with diethyl ether (5 ml).
× 2) to obtain 3.00 g (6.99 mmol) of the title compound (yield: 63%). 1H-NMR (CDCl ₃ , 270 MHz): δ 1.25 (3H, d, J = 7.0 Hz), 1.4-
2.1 (4H, m), 2.3-3.2 (6H, m),
3.65 (1H, m), 7.70 (2H, d, J = 8.
0 Hz), 8.05 (2H, d, J = 8.0 Hz). Enantiomeric excess: 40% ee

Example 3 (R) -2-methyl-1- (4-ethylphenyl) -3
Synthesis of -piperidino-1-propanone hydrochloride (Compound No. 3)

Embedded image Under an argon atmosphere, molecular sieves 3A13.3
2 g of lanthanoid triflate [La (OTf) ₃
• nH2O (n = 8-9)], 0.648 g,
9 ml of a 1 M (R) -ALB tetrahydrofuran solution was added, and tetrahydrofuran was distilled off under reduced pressure. 40 ml of toluene was added, and 1.15 g (8.9 mmol) of piperidinomethyl methyl ether was added. Further 1-
1.44 g of (4-ethylphenyl) -propanone (8.
9 mmol) and stirred at room temperature for 28 hours.

The molecular sieves were filtered off from the reaction suspension, extracted with 36 ml of 5N hydrochloric acid three times, and the aqueous layer was washed with dichloromethane (12 ml × 2). The aqueous layer was neutralized with 480 ml of a 5% aqueous ammonia solution while cooling, and extracted with dichloromethane (120 ml × 3). The organic layer was washed with 120 ml of saturated saline, and dried over anhydrous sodium sulfate 12 ml.
g. 4N hydrochloric acid / dioxane solution 10m under ice cooling
1 was added dropwise and stirred at room temperature for 1 hour. The crystals obtained by evaporating the solvent under reduced pressure were washed with n-hexane (5 ml ×
2), 1.42 g (4.8 mmol) of the title compound were obtained (54% yield). 1H-NMR (CDCl ₃ , 270 MHz): δ 1.13 (3H, t, J = 7.0 Hz), 1.27
(3H, d, J = 7.0 Hz), 1.4-2.2 (6
H, m), 2.3-3.2 (6H, m), 2.82 (2
H, q, J = 7.0 Hz), 3.64 (1H, m),
7.70 (2H, d, J = 8.0 Hz), 8.05 (2
H, d, J = 8.0 Hz). Enantiomeric excess: 35% ee

Example 4 (R) -2-methyl-1- (4-ethylphenyl) -3
-Pyrrolidino-1-propanone hydrochloride (Compound No. 4)
Synthesis of

Embedded image Under nitrogen atmosphere, molecular sieves 3A 11.1 g
Lanthanoid triflate [La (OTf) ₃ · n
H2O (n = 8-9)], 0.54 g, and 0.074 g
10 ml of a tetrahydrofuran solution of M (R) -ALB was added, and tetrahydrofuran was distilled off under reduced pressure. Toluene (32.5 ml) was added, and pyrrolidinomethyl methyl ether (1.20 g, 7.4 mmol) was added. One more
-(4-ethylphenyl) -propanone 0.85 g
(7.4 mmol) was added and the mixture was stirred at room temperature for 36 hours.

The molecular sieves were filtered off from the reaction suspension, extracted three times with 30 ml of 5N hydrochloric acid, and the aqueous layer was washed with ethyl acetate (10 ml × 2). 5 while cooling the water layer
The mixture was neutralized with 400% aqueous ammonia and extracted with ethyl acetate (100 ml × 3). The organic layer was washed with 100 ml of saturated saline and dried with 10 g of anhydrous sodium sulfate. Under ice-cooling, 30 ml of a 10% methanolic hydrochloric acid solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. The crystals obtained by evaporating the solvent under reduced pressure were washed with ethyl acetate (5 ml × 2) to obtain 1.06 g (3.77 mmol) of the title compound (yield: 51).
%). 1H-NMR (CDCl ₃ , 270 MHz): δ 1.12 (3H, t, J = 7.0 Hz), 1.27
(3H, d, J = 7.0 Hz), 1.4-2.1 (4
H, m), 2.3-3.2 (6H, m), 2.82 (2
H, q, J = 7.0 Hz), 3.64 (1H, m),
7.71 (2H, d, J = 8.0 Hz), 8.05 (2
H, d, J = 8.0 Hz). Enantiomeric excess: 33% ee

Example 5 (R) -2-methyl-1- (4-methylphenyl) -3
-Piridino-1-propanone hydrochloride (Compound No. 5)
Synthesis of

Embedded image Under nitrogen atmosphere, molecular sieves 3A 11.1 g
Lanthanoid triflate [La (OTf) ₃ · n
H2O (n = 8-9)], 0.54 g, and 0.074 g
10 ml of a tetrahydrofuran solution of M (R) -ALB was added. Tetrahydrofuran / diethyl ether = 1 /
1 (v / v) of a mixed solvent (32.5 ml) was added, and piperidinomethyl methyl ether (0.96 g, 7.4 mmol) was added.
l) was added. Further, 1.10 g (7.4 mmol) of 1- (4-methylphenyl) -propanone was added, and the mixture was stirred at room temperature for 36 hours.

The molecular sieves were filtered off from the reaction suspension, extracted three times with 30 ml of 5N hydrochloric acid, and the aqueous layer was washed with diethyl ether (10 ml × 2). The aqueous layer was neutralized with 400 ml of a 5% aqueous ammonia solution while cooling, and extracted with diethyl ether (100 ml × 3). The organic layer was washed with 100 ml of saturated saline and dried with 10 g of anhydrous sodium sulfate. Under ice cooling, 10 ml of a 4N hydrochloric acid / dioxane solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. The crystals obtained by evaporating the solvent under reduced pressure were washed with diethyl ether (5.
ml × 2), 1.18 g (4.2 mmol) of the title compound
Was obtained (yield 57%). 1H-NMR (CDCl ₃ , 270 MHz): δ 1.27 (3H, d, J = 7.0 Hz), 1.4-
2.2 (6H, m), 2.27 (3H, s), 2.3-
3.2 (6H, m), 3.55 (1H, m), 7.70
(2H, d, J = 8.0 Hz), 8.05 (2H, d,
J = 8.0 Hz). Enantiomeric excess: 35% ee

Examples 6 to 10 Hereinafter, in Examples 6 to 10, the same operation as in Example 2 was performed.
Compound Nos. 6-10 were prepared (Table 1).

[Table 1]

Example 11 (R) -3-phenyl-5- {2- (pyrrolidinylmethyl) butyryl} isoxazole hydrochloride (Compound No. 1)
Synthesis of 1)

Embedded image Under a nitrogen atmosphere, molecular sieves 3A 25.0 g
Lanthanoid triflate La (OTf) ₃ · n
Add 1.62 g of H2O (n = 8-9), add 0.1M
22.2 ml of a tetrahydrofuran solution of (R) -ALB
And tetrahydrofuran was distilled off under reduced pressure. 100 ml of toluene was added, and 2.56 g (22.2 mmol) of pyrrolidinomethyl methyl ether was added. Further, 3.78 3-phenyl-5-butyryl isoxazole
g (22.2 mmol) was added and stirred at room temperature for 36 hours.

The molecular sieves were filtered off from the reaction suspension, extracted three times with 50 ml of 5N hydrochloric acid, and the aqueous layer was washed with ethyl acetate (30 ml × 2). 5 while cooling the water layer
The mixture was neutralized with 700 ml of an aqueous ammonia solution and extracted with dichloromethane (300 ml × 3). The organic layer was washed with 200 ml of saturated saline, and the crude product obtained by evaporating the solvent under reduced pressure was dissolved in 10 ml of dichloromethane, and 10 ml of a 10% aqueous hydrochloric acid solution was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Stirred. After liquid separation, the organic layer was dried over anhydrous sodium sulfate (20 g), ethyl acetate (20 ml) was added, and the mixture was stirred at 5 ° C for 1 hour. The crystals were collected by filtration, washed with ethyl acetate (5 ml ×
2), 3.12 g (9.32 mmol) of the title compound were obtained (82% yield). 1H-NMR (CDCl ₃ , 270 MHz): δ 0.99 (3H, t, J = 7.3 Hz), 1.77
-1.83 (1H, m), 1.88-1.97 (1H,
m), 1.98-2.11 (2H, m), 2.11
2.23 (2H, m), 2.70-2.78 (1H,
m), 2.79-2.95 (1H, m), 3.33 (1
H, m), 3.47-3.64 (1H, m), 3.68
-3.71 (1H, m), 3.83-3.87 (1H,
m), 4.33-4.38 (1H, m), 7.48-
7.50 (3H, m), 7.76 (1H, s), 7.8
7-7.90 (2H, m). Enantiomeric excess: 42% ee

Example 12 Synthesis of (S) -3-phenyl-5- {2- (piridinylmethyl) propionyl} isoxazole hydrochloride (Compound No. 12)

Embedded image Under nitrogen atmosphere, molecular sieves 3A30.0g
Lanthanoid triflate La (OTf) ₃ · n
Add 1.62 g of H2O (n = 8-9), add 0.1M
22.2 ml of a tetrahydrofuran solution of (S) -ALB
And tetrahydrofuran was distilled off under reduced pressure. 100 ml of toluene was added, and 2.87 g (22.2 mmol) of piperidinomethyl methyl ether was added. 3. 3-phenyl-5-propionyl isoxazole;
47 g (22.2 mmol) was added and the mixture was stirred at room temperature for 28 hours.

The molecular sieves were filtered off from the reaction suspension, extracted three times with 50 ml of 5N hydrochloric acid, and the aqueous layer was washed with ethyl acetate (30 ml × 2). 5 while cooling the water layer
The mixture was neutralized with 700 ml of an aqueous ammonia solution and extracted with dichloromethane (300 ml × 3). The organic layer was washed with saturated saline (200 ml), dried over anhydrous sodium sulfate (20 g), and the solvent was distilled off under reduced pressure to give the title compound (4.11 g).
(13.76 mmol) as white crystals (yield 6).
2%). Melting point 114-116 ° C 1H-NMR (CDCl ₃ , 270 MHz): δ1.3 (3H, d, J = 6 Hz), 1.5-1.8.
(6H, m), 2.3-3.0 (6H, m), 3.5-
4.0 (1H, m), 7.2 (1H, s), 7.5-
7.7 (3H, m), 7.7-8.0 (2H, m). Enantiomeric excess: 30% ee

Examples 13 to 18 The same procedures as in Example 11 were carried out in Examples 13 to 18 to produce Compound Nos. 13 to 18 (Table 2).

[Table 2]

[0036]

Industrial Applicability The present invention relates to an optically active α-substituted-β-aminoketone derivative having a central muscle relaxing action, which is useful as a pharmaceutical, and an optically active lanthanum-alkali metal-binaphthol which is a multifunctional complex metal complex. This is an effective method in which an asymmetric Mannich reaction using an α-amino ether using a complex as a catalyst is directly performed in one step from optically inactive starting materials. The method of the present invention is industrially excellent because it is not necessary to remove unnecessary optical isomers by optical resolution after synthesizing a racemate as in a known method.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) C07D 275/02 C07D 275/02 275/03 295/10 Z 295/10 C07B 61/00 300 // C07B 61 / 00 300 C07M 7:00 (72) Inventor Takayoshi Arai 3-4-25 Aow Shinke, Minoh-shi, Osaka Sunny Court (I) 102 (72) Inventor Masakatsu Shibasaki 2-1-21-2 Shimorenjaku, Mitaka-shi, Tokyo F Term (reference) 4C033 AA04 AA05 AA18 4C056 AA01 AB01 AC01 AD01 AE03 AF10 FA04 FA13 FB01 FC01 4G069 AA06 BA27A BA27B BA44A BC04A BC04B BC16A BC16B BC39A BC40A BC42A BD02A BD02B BD08A BE08B BAA BDA BA45 BA67 BA71 BJ50 BR30 BU32 4H039 CA19 CD10 CD40

Claims (5)

[Claims] 1. An optically active aluminum-alkali metal-
Performing an asymmetric Mannich reaction using a binaphthol complex, a Lewis acid, and an α-aminoether derivative, an optically active α-
A method for producing a substituted-β-aminoketone derivative. 2. An optically active aluminum-alkali metal-
The binaphthol complex is represented by the general formula (1) [general formula (1-1)
And (1-2)]: The method according to claim 1, which is a compound represented by the formula: 3. A Lewis acid having the general formula (2): The method according to claim 1, wherein the compound is a compound represented by the formula: wherein M represents a lanthanum atom, a ytterbium atom or a scandium atom, and m is a positive integer. 4. An α-amino ether derivative represented by the following general formula (3): [Wherein, R1 represents a lower alkyl group, a phenyl group or a benzyl group, R2 and R3 independently represent a saturated or unsaturated lower alkyl group, or R2 and R3 become one to form a general formula (4) ] (In the formula, n is 0 or an integer of 1 to 2, and Z represents an oxygen atom, a methylene group, an amino group, a methylamino group, or a benzylamino group.) The method according to any one of claims 1 to 3, which is a compound represented by the formula: 5. An optically active α-substituted-β-aminoketone derivative represented by the following general formula (5): In the formula, R4 is a group represented by the general formula (6) [general formulas (6-1) and (6-2)]: (R6 is a halogen atom; a lower alkyl group; a benzyl group; a benzoyl group; a pyridyl group; a furyl group optionally substituted with a lower alkyl group; a thienyl group optionally substituted with a lower alkyl group; a halogen atom, a lower alkoxy group , Trifluoromethyl group, cyano group, nitro group, amino group,
A phenyl group or a naphthyl group optionally substituted with a dimethylamino group, an acetamido group, a methanesulfonylamido group, an acetyl group or a lower alkoxycarbonyl group: R7 represents a trifluoromethyl group or a lower alkyl group;
Y represents an oxygen atom or a sulfur atom), and R2 represents a lower alkyl group; a benzyl group; a methoxy group; a phenyl group;
An allyl group; an alkyl group substituted with a trifluoromethyl group or a lower alkoxy group; or a cyclopropylmethyl group, R3 and R4 each independently represent a saturated or unsaturated lower alkyl group, or R3 and R4 become one And the general formula (4): (In the formula, n represents 0 or an integer of 1 to 2, and Z represents a methylene group, an oxygen atom, an amino group, a methylamino group, or a benzylamino group.) ｝
The production method described in 1.