JPH0379348B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field) The present invention relates to a novel optically active α-monoalkylamino-ε-caprolactam and a method for producing the same.

Optically active α-monoalkylamino-ε-caprolactam is a compound useful as an optical resolution agent.

(Background technology) For compounds used as medicines and agricultural chemicals, amino acids, fatty acids, etc., optically active forms of (-) form or (+) form are often effective, and therefore, optical resolution in the manufacturing process of these substances is often effective. In many cases, separation into optically active forms by agents plays an important role.

As optical resolving agents for basic compounds, inexpensive ones such as tartaric acid and malic acid are used, but as basic resolving agents necessary for optical resolution of acidic compounds, natural agents such as quinine, brucine, and efuedrin are used. The only known substances are phenethylamine and phenethylamine, and these are often expensive.

(Purpose) Therefore, the present inventors conducted extensive studies with the aim of providing a novel optically active compound that can be used as an inexpensive basic resolving agent using optically active raw materials that can be produced at a relatively low cost. invention has been achieved.
Furthermore, as a result of intensive studies aimed at providing a method for producing such novel optically active compounds, the present inventors discovered a method for selectively monoalkylating primary amines while retaining the optical activity of the raw materials. Ta. The inventors have discovered that the novel optically active compound of the present invention can be produced by this method, and have arrived at the present invention.

(Structure) That is, the present invention has the following general formula () (In the formula, R represents a methyl group, an ethyl group, or a propyl group.) These are optically active α-monoalkylamino-ε-caprolactams and salts thereof.

In addition, the present invention also provides the following formula () by reacting optically active α-amino-ε-caprolactam with benzaldehyde. An optically active α-phenylmethyleneamino-ε-caprolactam represented by is obtained, the α-phenylmethyleneamino-ε-caprolactam is reacted with an alkylating agent, and then hydrolyzed in the presence of an acid. The following general formula () is characterized by (In the formula, R represents a methyl group, an ethyl group, or a propyl group.) This is a method for producing optically active α-monoalkylamino-ε-caprolactam.

(Characteristics) The first feature of the present invention is optically active α-monoalkylamino-ε-caprolactam as a new substance. It is useful as a drug.

Further, the second feature of the present invention is α-amino-ε
- A method for selectively monoalkylating the N-position of caprolactam. α-monoalkylamino-
ε-caprolactam is a compound obtained by monoalkylating the N-position of α-amino-ε-caprolactam, but the conditions for selective monoalkylation of the N-position are not yet known. This is because when α-amino-ε-caprolactam is alkylated, general alkylation conditions cannot be applied because there are four positions to be alkylated and many products may be produced as by-products.

Furthermore, in general, when primary amino groups are alkylated, a mixture of the primary amine as a raw material, the secondary amine as the target product, and the tertiary amine as a by-product is produced even if measures such as controlling the molar ratio are used. , very difficult to separate. It is also well known that the functional groups of lactams are relatively easily methylated to give N-methyl or O-methyl derivatives.

However, according to the method of the present invention, it is surprisingly possible to completely control the above-mentioned side reactions, and it is difficult to selectively introduce one alkyl group into the N-position of α-amino-ε-caprolactam. It is possible to selectively introduce lower alkyl groups, which are considered to be effective, in extremely high yields.

Furthermore, the third feature of the present invention is α-amino-ε
- When selectively monoalkylating the N-position of caprolactam, the reaction can be carried out while completely retaining the optical activity of the raw material, so the optically active α-amino-ε
Optically active α-monoalkylamino-ε-caprolactam ((-) form or (+) form) can be obtained in extremely high yield from -caprolactam ((-) form or (+) form).

(Description of Structure) The present invention will be specifically explained below. First, the method of the present invention will be described, and then the compound of the present invention will be described.

First, prepare the raw materials.

Optically active α-phenylmethyleneamino-ε represented by the above formula (), which is a raw material for the method of the present invention
-Caprolactam is an optically active α-amino-ε
- Obtained by reacting caprolactam with benzaldehyde.

The optically active α-amino-ε-caprolactam used here can be produced by any method. For example, amination of α-chloro-ε-caprolactam (Japanese Patent Publication No. 46-23747), reduction of α-nitro-ε-aminocaprolactam (Swiss Patent No. 375720), Becman of α-aminocyclohexanone oxime. Dislocation (Tokuko Showa 41-
Various production methods are known, including dealcoholization cyclization of lysine lower alkyl ester (Japanese Patent Publication No. 18089), and α-amino-ε-caprolactam produced by any of these methods. Available for use.

Optically active α-amino-ε-caprolactam obtained by any method can be used. For example, α-amino-ε-caprolactam produced by the method described above can be used.
Caprolactam can also be obtained by optical resolution using a suitable optical resolution agent.

Benzaldehyde, which is another raw material of the present invention, can be produced by a conventionally known method.

Next, optically active α-amino-ε-caprolactam and benzaldehyde are reacted to produce α-phenylmethyleneamino-ε-caprolactam (hereinafter abbreviated as Schiff base).

The aldehyde used here is (1) an active aldehyde that has the ability to form a Schiff base even at low temperatures to prevent racemization, and (2) it is used as a type of protecting group, so it can be recovered and used repeatedly after the purpose is achieved. (3) The aldehyde must be stable and usable; (3) It must satisfy conditions such as not having the risk of causing other side reactions in the subsequent alkylation step, such as not having an active hydrogen next to the aldehyde group. , and uses benzaldehyde.

The amount of benzaldehyde used is determined by the optically active α
-Amino-ε-caprolactam per mole
The amount is 1.0 to 10.0 mol, preferably 1.1 to 2.5 mol.

As a method for producing Schiff base, a general method can be adopted. Since the Schiff base formation reaction is an equilibrium reaction as shown in the following equation (), it is generally devised to remove the generated water by some method.

R−NH ₂ +OHC−R′R−N=CH−R′+H ₂ O
() Specifically, (1) azeotropic removal of water produced using a solvent such as benzene or toluene, (2) coexistence of a dehydrating agent such as molecular sieve, and (3) a solvent that is immiscible with water. There are methods such as layer separation and removal of the generated water using a method, and any of these methods can be adopted as the method of the present invention.

The solvent used here varies depending on the method used to remove the generated water as described above, but preferably a water-insoluble solvent, especially an aromatic hydrocarbon solvent such as benzene or toluene. Preferably used. The amount of solvent used depends on the optically active α-amino-ε-caprolactam raw material.
2.0 to 30 times the weight.

The reaction temperature is 30-110°C, preferably 50-80°C. The reaction time varies depending on the reaction temperature, but
Generally 0.1-2.0 hours.

In particular, in order to proceed with the reaction while maintaining the optical activity of the raw materials and to prevent racemization, it is necessary to employ conditions as mild as possible. As a safe guideline, the relationship between reaction temperature and reaction time shown in the following equation () may be observed.

T: Reaction time (hr) t: Reaction temperature (°C) That is, when carried out at 80°C, racemization will not occur if the reaction is completed within 1 hour. Of course, since the reaction of the present invention is very fast, the reaction can be sufficiently completed under these conditions. At that time, the reaction temperature and reaction time are preferably selected from 70 to 90°C and 2 to 0.5 hours, respectively.

Although the Schiff base formation reaction is generally accelerated by an acid catalyst, the purpose of the present invention can be sufficiently achieved without the use of a catalyst.

The Schiff base is isolated from the Schiff base-containing reaction mixture thus obtained, or the reaction mixture as it is without isolation, or the reaction mixture is concentrated and subjected to an alkylation reaction. Any method can be used to isolate Schiff's base from the reaction mixture, but since there are almost no other by-products in the reaction mixture, isolation by removing the solvent from the reaction mixture is preferable. It is the simplest.

In the subsequent alkylation reaction, the Schiff base is reacted with an alkylating agent.

The alkylating agent used here is not particularly limited, but examples of reagents that can be smoothly alkylated under mild conditions include methyl iodide, ethyl iodide, propyl iodide, methyl bromide, ethyl bromide, Alkyl halides such as propyl bromide, dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, and dipropyl sulfate are preferably used. The amount of alkylating agent used is 1.0 to 5.0 to Schiff base.
twice the molar amount, preferably 1.0 to 2.0 times the molar amount.

What should be noted in this step is the simultaneous occurrence of hydrolysis reactions. Therefore, general measures are required to prevent water from entering the reaction system.

Furthermore, when obtaining an optically active final product, care must be taken not to cause a racemization reaction as well. The racemization reaction is selected from the above-mentioned ranges for the reaction temperature and reaction time while satisfying the relationship of the conditional guideline formula () between the reaction temperature and reaction time shown in the Schiff base production process described above. By adopting these conditions, it is possible to prevent their occurrence. Of course, the desired reaction can be achieved within the intended conditions. As for other conditions, general conditions using an alkyl halide or a dialkyl sulfate as an alkylating agent can be applied.

In this way, for example, a reaction intermediate represented by the following formula () is produced in the form of a salt.

This reaction intermediate (2) is not isolated, but is subjected to a hydrolysis reaction in the reaction mixture as it is or after appropriately concentrating the reaction mixture.

This reaction requires sufficient water and catalyst amount, 0.01~
With 5.0 moles of acid, preferably 0.5 to 3.0 moles,
The process is completed in 0.1 to 1 hour at room temperature. In order to accelerate the reaction rate, the reaction can also be carried out under slight heating conditions, for example at 30 to 50°C. As the catalyst, mineral acids such as hydrochloric acid, sulfuric acid, and monomethyl sulfuric acid, and organic acids such as acetic acid and oxalic acid are preferably used.

The reaction intermediate () is thus hydrolyzed to produce optically active α-monoalkylamino-ε-caprolactam and benzaldehyde.

After the reaction, the optically active α-monoalkylamino-ε-caprolactam, which is the target substance, exists in the form of a salt, so if it is extracted with a water-insoluble organic solvent such as benzene or chloroform, the benzaldehyde can be separated from the organic layer. can be easily separated.
The target product remaining in the aqueous layer can be extracted after neutralization, or can be directly subjected to ion exchange treatment, or other general amine isolation methods can be applied under mild conditions.

The optically active α-monoalkylamino-
ε-caprolactam can be purified, for example, by recrystallization from an organic solvent such as a mixed solvent of ethyl acetate and cyclohexane.

The optically active α-monoalkylamino-
Both the (+) and (-) forms of ε-caprolactam are white crystals. In this compound, only one hydrogen of the amino group is selectively lower-alkylated,
It is particularly useful as an optical resolution agent for acidic compounds.

The present invention will be explained below with reference to Examples.

Example 1 21.6 g (0.1 mol) of (-)-α-phenylmethyleneamino-ε-caprolactam and 37.8 g (0.3 mol) of dimethyl sulfate purified by distillation were placed in a 200 ml flask and heated at 90°C for 20 minutes with stirring. Made it react. After the reaction is complete, cool with ice water and add 100% water.
ml was added to make a homogeneous solution. 1N hydrochloric acid aqueous solution
100 ml was added and further stirred for 1 hour.

After the reaction mixture was extracted twice with 50 ml of chloroform, the aqueous layer was passed through an ion exchange resin (Diaion PK220H type, manufactured by Mitsubishi Kasei, 200 ml) and thoroughly washed until neutral. It was eluted with a 5% ammonia aqueous solution and concentrated under reduced pressure to obtain 13.5 g of crude (-)-α-monomethylamino-ε-caprolactam. The yield is
It was 94.8%. Further, it was recrystallized from a mixed solvent of ethyl acetate and cyclohexane to obtain purified (-)-α-monomethylamino-ε-caprolactam. on the other hand,
The chloroform layer was concentrated under reduced pressure and then distilled under reduced pressure to recover 9.2 g of benzaldehyde.

The obtained (-)-α-monomethylamino-ε-
The physical properties of caprolactam were as follows.

Elemental analysis (as _C7H14N2O ) C% H% N% Analytical value _{59.07 9.94} 19.75 Calculated value 59.12 9.92 19.70 Melting point 100-101℃ ^2H nuclear magnetic resonance spectrum ( _D2O solvent) 1.4-2.2ppm ( 6H) 2.4ppm (3H) 3.3-3.7ppm (3H) Optical rotation [α] ^23.5 _D -39.44 (C = 3.9 1N HCl aq) -45.45 (C = 3.9 H ₂ O) Example 2 In a 500 ml flask ( +)-α-Amino-ε-caprolactam 25.6 g (0.20 mol), benzaldehyde 25.4 g (0.24 mol) and benzene 300 ml were charged, and an azeotropic dehydration device was installed and heated. After the reaction started for 30 minutes, benzene was distilled off under reduced pressure.

75.6 g (0.60 mol) of dimethyl sulfate was added to the concentrate, and the mixture was reacted at 80° C. for 25 minutes. After the reaction was completed, hydrolysis reaction and isolation were carried out in the same manner as in Example 1 to obtain 27.8 g of crude (+)-α-monomethylamino-ε-caprolactam. The yield was 97.9%. The obtained crude product was further recrystallized from ethyl acetate to obtain purified (+)-α-monomethylamino-ε-caprolactam.

The obtained (+)-α-monomethylamino-ε-
The physical properties of caprolactam were as follows.

Elemental analysis (as _C7H14N2O ) C% H% N% Analytical value _{59.08 9.94} 19.81 Calculated value 59.12 9.92 19.70 Melting point 100-101℃ ^2H nuclear magnetic resonance spectrum ( _D2O solvent) 1.4-2.2ppm ( 6H) 2.4ppm (3H) 3.3-3.7ppm (3H) Optical rotation [α] ^23.5 _D +39.54 (C = 4.1 1N HCl aq) +44.08 (C = 3.9 H ₂ O) Example 3 (-) -α-phenylmethyleneamino-ε-caprolactam 21.6 g (0.1 mol), n-propyl bromide 27.5 g (0.12 mol) and benzene 100
ml was placed in a 300 ml flask and heated under reflux for 5 hours. After the reaction was completed, the mixture was cooled with ice water, 100 ml of a 2N aqueous hydrochloric acid solution was added, and the mixture was stirred for 1 hour.

Then, isolation was carried out in the same manner as in Example 1 to obtain crude (-)
-α-monopropylamino-ε-caprolactam
14.7g was obtained. The yield was 86.5%. Further vacuum distillation was performed to obtain purified (-)-α-monopropylamino-ε-caprolactam as a fraction with a boiling point of 106°C/0.18mmHg.

The obtained (-)-α-monopropylamino-ε
-The physical properties of caprolactam were as follows.

Elemental analysis ( _{as C9H18N2O} ) C% H% N% Analytical value _63.64 10.52 16.44 Calculated value 63.49 10.66 16.45 Boiling point 106℃/0.18mmHg ^2H nuclear magnetic resonance spectrum ( _D2O solvent) 0.9-1.2ppm (3H) 1.5-2.4ppm (8H) 2.9-3.5ppm (4H) 4.1-4.5ppm (1H) Optical rotation [α] ^22.0 _D -42.55 (C = 2.5 H ₂ O) Example 4 In Example 3, the raw materials As(+)-α-phenylmethyleneamino-ε-caprolactam 21.6
14.8 g of crude (+)-α-monopropylamino-ε-caprolactam was obtained.
The yield was 87.1%. Distilled under reduced pressure in the same manner as in Example 3 to obtain purified (+)-α-monopropylamino-
ε-caprolactam was obtained.

The obtained (+)-α-monopropylamino-ε
-The physical properties of caprolactam were as follows.

Elemental analysis ( _{as C9H18N2O} ) C% H% N% Analytical value _63.37 10.71 16.52 Calculated value 63.49 10.66 16.45 Boiling point 106℃/0.18mmHg ^2H nuclear magnetic resonance spectrum ( _D2O solvent) 0.9-1.2ppm (3H) 1.5-2.4ppm (8H) 2.9-3.5ppm (4H) 4.1-4.5ppm (1H) Optical rotation [α] ^22.0 _D +42.32 (C = 2.6 H ₂ O) Example 5 (+) - α 2.9 g (0.01 mol) of -phenylmethyleneamino-ε-caprolactam and 7.7 g (0.05 mol) of diethyl sulfate purified by distillation were placed in a 100 ml flask and stirred at 90°C for 20 minutes.

After the reaction is complete, cool with ice water and add 10ml of water.
The mixture was further stirred for 1 hour. After the reaction mixture was extracted twice with 20 ml of chloroform, the aqueous layer was treated in the same manner as in Example 1 to obtain crude (+)-α-monoethylamino-
1.4 g of ε-caprolactam was obtained. Yield is 89.7%
It was hot. Further distillation under reduced pressure has a boiling point of 127℃/0.2mm.
0.9 g of purified (+)-α-monoethylamino-ε-caprolactam was obtained as a Hg fraction.

The obtained (+)-α-monoethylamino-ε-
The physical properties of caprolactam were as follows.

Elemental analysis ( _{as C8H16N2O} ) C% H% N% Analytical value _61.37 10.56 17.71 Calculated value 61.50 10.32 17.93 Boiling point 127℃/0.2mmHg ^2H nuclear magnetic resonance spectrum ( _D2O solvent) 1.1-1.4ppm (3H) 1.4-2.4ppm (6H) 2.7-3.5ppm (4H) 4.0-4.4ppm (1H) Optical rotation [α] ^21.5 _D +40.82 (C = 2.0 H ₂ O) Example 6 In Example 5, As a raw material (-)-α-phenylmethyleneamino-ε-caprolactam 2.9
1.35 g of crude (-)-α-monoethylamino-ε-caprolactam was obtained. The yield was 86.6%. Distilled under reduced pressure in the same manner as in Example 5 to obtain purified (-)-α-monoethylamino-ε-
Obtained caprolactam.

The obtained (-)-α-monoethylamino-ε-
The physical properties of caprolactam were as follows.

Elemental analysis ( _{as C8H16N2O} ) C% H% N% Analytical value _61.77 10.41 19.82 Calculated value 61.50 10.32 17.93 Boiling point 127℃/0.2mmHg ^2H nuclear magnetic resonance spectrum ( _D2O solvent) 1.1-1.4ppm (3H) 1.4~2.4ppm (6H) 2.7~3.5ppm (4H) 4.0~4.4ppm (1H) Optical rotation [α] ^21.5 _D −40.79 (C=2.0 H ₂ O) Example 7 (±) −α− 21.6 g (0.1 mol) of phenylmethyleneamino-ε-caprolactam and 37.8 g (0.3 mol) of dimethyl sulfate purified by distillation were placed in a 200 ml flask, and reacted with stirring at 90° C. for 30 minutes.

After the reaction was completed, 12.8 g of α-methylamino-ε-caprolactam was obtained in the same manner as in Example 1.

Claims (1)

[Claims] First-order general formula () (In the formula, R represents a methyl group, an ethyl group, or a propyl group.) An optically active α-monoalkylamino-ε-caprolactam and a salt thereof. 2 React optically active α-amino-ε-caprolactam with benzaldehyde to form the following formula () An optically active α-phenylmethyleneamino-ε-caprolactam represented by is obtained, the α-phenylmethyleneamino-ε-caprolactam is reacted with an alkylating agent, and then hydrolyzed in the presence of an acid. The following general formula () is characterized by (In the formula, R represents a methyl group, an ethyl group, or a propyl group.) A method for producing optically active α-monoalkylamino-ε-caprolactam.