JPH11171860A - Method for producing optically active N-substituted azetidine-2-carboxylic acid - Google Patents

Abstract

(57) Abstract: An industrially advantageous method for producing optically active azetidine-2-carboxylic acid is provided. SOLUTION: General formula (1) (Wherein, Ns is a 2-nitrobenzenesulfonyl group,
Represents a nitrobenzenesulfonyl group or a 2,4-dinitrobenzenesulfonyl group, and * represents an asymmetric carbon atom)
Reacting an optically active N-substituted azetidine-2-carboxylic acid with thiophenol or phenol in the presence of an amine.
-A process for producing carboxylic acids.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing optically active azetidine-2-carboxylic acid.

[0002]

2. Description of the Related Art Optically active azetidine-2-carboxylic acid is an important compound as a raw material for pharmaceuticals. As a conventional method for producing such optically active azetidine-2-carboxylic acid, for example, a method in which an optically active N-tosyl-azetidine-2-carboxylic acid is eliminated from the tosyl group by Birch reduction (Japanese Patent Application Laid-Open No. 47-14457). However, in this method, there is a problem of safety such as ignition because metal Na is indispensable, and a step of removing inorganic salts generated after completion of the reaction with an ion exchange resin or the like and purifying is required. For this reason, it was difficult to say that this method was industrially advantageous.

[0003]

SUMMARY OF THE INVENTION Accordingly, the present inventors
As a result of intensive studies on a method for producing an optically active azetidine-2-carboxylic acid which is more industrially advantageous, it has been found that an optically active N-substituted azetidine-2-carboxylic acid having a specific substituent can be obtained in the presence of an amine. -It has been found that carboxylic acid can be led to the present invention.

[0004]

That is, the present invention provides a compound represented by the following general formula (1): (Wherein, Ns is a 2-nitrobenzenesulfonyl group,
Represents a nitrobenzenesulfonyl group or a 2,4-dinitrobenzenesulfonyl group, and * represents an asymmetric carbon atom)
Reacting an optically active N-substituted azetidine-2-carboxylic acid with thiophenol or phenol in the presence of an amine.
A method for producing a carboxylic acid.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION As the optically active N-substituted azetidine-2-carboxylic acid represented by the general formula (1), (S)-
N-2-nitrobenzenesulfonylacetidine-2-carboxylic acid, (S) -N-4-nitrobenzenesulfonylacetidine-2-carboxylic acid, (S) -N-2,4-dinitrobenzenesulfonylacetidine-2-carboxylic acid Carboxylic acid, (R) -N-2-nitrobenzenesulfonylacetidine-2-carboxylic acid, (R) -N-4-nitrobenzenesulfonylacetidine-2-carboxylic acid, (R) -N
-2,4-dinitrobenzenesulfonylacetidine-2
-Carboxylic acids.

Such an optically active N-substituted azetidine-2-carboxylic acid has, for example, the general formula (2): (Wherein, Ns and * have the same meanings as described above, R represents a lower alkyl group, and X represents a halogen atom, respectively). It can be produced by hydrolyzing after ring closure below. Here, in the general formula (2), the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, and the halogen atom includes chlorine, bromine, iodine atom and the like. Examples of the base include alkali metal hydrides such as sodium hydride and lithium hydride, alkali metal alcoholates such as sodium methylate and sodium ethylate, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. No.

The desired optically active azetidine-2-carboxylic acid can be produced by reacting the optically active N-substituted azetidine carboxylic acid with thiophenol or phenol in the presence of an amine.

The amine used in the present invention includes:
Examples thereof include aliphatic amines, alicyclic amines, and aromatic amines. Among them, aliphatic amines are preferable. The aliphatic amine may be any of a primary amine, a secondary amine and a tertiary amine. In the secondary and tertiary amines, each alkyl group may be the same or different. Among these aliphatic amines, lower alkylamines whose alkyl groups are all linear or branched lower alkyl groups having 1 to 6 carbon atoms are easily removed when excess amine is removed after the reaction. Is preferred.

As such lower alkylamines, there are
Examples of the secondary amine include methylamine, ethylamine, n-propylamine, isopropylamine, butylamine, isobutylamine, tert-butylamine, n-pentylamine, and sec-pentylamine. Examples of the secondary amine include dimethylamine, diethylamine, Jee
n-propylamine, di-n-butylamine, di-n-
Examples of pentylamine, methylethylamine, methylpropylamine and the like, and examples of the tertiary amine include trimethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, methyldiethylamine and the like.

[0010] Of the above-mentioned lower alkylamines, lower alkylamines having a boiling point of about room temperature or higher are more preferable from the viewpoint of handling, and when a solvent is used in the present invention, it has a boiling point lower than the boiling point of the solvent used. Lower alkylamines are more preferable from the viewpoint that excess amine can be easily separated from the solvent used. For example, when a solvent as described later in the present invention is used, among lower alkylamines, n-propylamine, n-butylamine, n-pentylamine, diethylamine, di-n-propylamine, triethylamine, tri-n-
Propylamine and the like are particularly preferred.

In the present invention, the above-mentioned amines may be used alone or in combination of two or more. When two or more are used in combination, there is no particular limitation on the order of use. The amount of the amine to be used is generally in the range of about 1 to 50 moles per mol of the optically active N-substituted azetidine-2-carboxylic acid, and when two or more kinds are used in combination, the total amount may be within the above range. .

In the present invention, the amount of thiophenol or phenol used may be at least the amount of the optically active N-substituted azetidine-2-carboxylic acid, and the upper limit thereof is from the viewpoint of economic efficiency. -It may be about 10 mole times the carboxylic acid. From the viewpoint of reaction efficiency, the amount of thiophenol or phenol used is preferably in excess of the optically active N-substituted azetidine-2-carboxylic acid, and more preferably in the range of about 1.1 to 2 moles. Thiophenol is more preferred from the viewpoint of the reaction rate.

The reaction may be carried out in the above-mentioned amine, but is usually carried out in a solvent. Examples of such a solvent include ethers such as tetrahydrofuran, ethyl ether, isopropyl ether, tert-butyl ether, dioxane and dimethoxyethane. Solvents, amide solvents such as dimethylformamide, halogen solvents such as dichloromethane, dichloroethane and chloroform, aromatic hydrocarbon solvents such as toluene, and aprotic polar solvents such as dimethyl sulfoxide can be exemplified. Each of these solvents may be used alone or in combination of two or more. The amount of the solvent used is usually about 2 to 50 times by weight based on the optically active N-substituted azetidine-2-carboxylic acid from the viewpoint of reaction rate and economic efficiency. is there.

The reaction temperature may be generally 0 ° C. or higher, and the upper limit thereof is not particularly limited, but may be about 100 ° C., preferably in the range of 25 ° C. to 60 ° C. The end point of the reaction may be appropriately determined by a commonly used analysis method or the like.

Thus, the optically active azetidine-2-carboxylic acid can be obtained. The obtained optically active azetidine-2-carboxylic acid may be separated and recovered, or the obtained optically active azetidine-2-carboxylic acid can be obtained. When producing another compound from the above, the reaction solution may be used in another step as it is. The separated and recovered optically active azetidine-2-carboxylic acid may be further purified by a commonly used method such as column chromatography or recrystallization.

Examples of the method for separation and recovery include a method of filtering a precipitate deposited during the reaction and recrystallization, and a method of adding a hydrophobic organic solvent such as ethyl acetate and water to the residue after distilling off the solvent after completion of the reaction. And recrystallization from the aqueous layer.

[0017]

According to the method of the present invention, optically active azetidine-2-carboxylic acid can be obtained by an industrially advantageous method.

[0018]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 1.0 g of (S) -N-2-nitrobenzenesulfonyl-azetidine-2-carboxylic acid (3.5 m
mol) was dissolved in 5 ml of dimethoxyethane, 4 ml (49 mmol) of n-propylamine was added at 30 ° C., and then 0.38 g (3.5 mmol) of thiophenol was gradually added dropwise, followed by stirring at room temperature for 12 hours. Next, the precipitate in the reaction solution was filtered and washed with 20 ml of ethyl acetate to obtain 1.23 g of pale yellow crystals. By recrystallizing 0.5 g of the crystal with 8.5 ml of ethanol, (S) -azetidine-2 was obtained.
-0.23 g of carboxylic acid (white crystals, yield 70%) was obtained.

Example 2 1.0 g of (S) -N-2-nitrobenzenesulfonyl-azetidine-2-carboxylic acid (3.5 m
mol) was dissolved in 10 ml of dimethylformamide, and 3
15 ml (108 mmol) of triethylamine at 0 ° C
After addition of 1.65 g of thiophenol (15 mmol
l) was gradually added dropwise, and the mixture was stirred at room temperature for 2 days. Next, the reaction solution was concentrated by an evaporator, and the obtained residue was 2.9.
g, 40 ml of ethyl acetate and 40 ml of water were added and the mixture was separated.
After concentrating the obtained aqueous layer to about 1.5 ml, adding 8.5 ml of ethanol and recrystallizing, 0.19 g of (S) -azetidine-2-carboxylic acid (white crystals, yield 53%, Optical purity of 99% ee or more) was obtained.

Example 3 1.0 g of (S) -N-2-nitrobenzenesulfonyl-azetidine-2-carboxylic acid (3.5 m
mol), 20 ml of n-propylamine and 1.77 g (17.5 mmol) of triethylamine were added to the solution.
0.46 g (4.2 mmol) of thiophenol at 0 ° C.
Was slowly added dropwise and stirred at room temperature for 3 hours. Then, the reaction solution was concentrated by an evaporator to obtain 1.85 g of a residue.
Then, 40 ml of ethyl acetate and 40 ml of water were added to the mixture, and the mixture was separated. The obtained aqueous layer was concentrated to about 1.5 ml, and then 9.5 ml of ethanol was added thereto for recrystallization, whereby (S) -azetidine-2- was obtained. 0.15 g of carboxylic acid (white crystals, yield 4
3% and an optical purity of 99% ee or more).

Claims (5)

[Claims] 1. The general formula (1) (Wherein, Ns is a 2-nitrobenzenesulfonyl group,
Represents a nitrobenzenesulfonyl group or a 2,4-dinitrobenzenesulfonyl group, and * represents an asymmetric carbon atom)
Reacting an optically active N-substituted azetidine-2-carboxylic acid with thiophenol or phenol in the presence of an amine.
-A process for producing carboxylic acids. 2. The method according to claim 1, wherein the amine is an aliphatic amine. 3. The method according to claim 2, wherein the aliphatic amine is a lower alkylamine. 4. The lower alkylamine is n-propylamine, n-butylamine, n-pentylamine, diethylamine, di-n-propylamine, triethylamine,
The production method according to claim 3, wherein the production method is at least one of tri-n-propylamine. 5. The amount of thiophenol or phenol used is 1.1 of optically active N-substituted azetidine-2-carboxylic acid.
2. The method according to claim 1, wherein the molar ratio is up to 2 times.