JPH10324673A - Production of n-substituted amino acid ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently produce the subject compound in high yield without carrying out complicated solid-liquid separating or solution replacing operations, etc., by protecting an amino group in amino acids with a protecting group, then extracting the resultant compounds with a specific solvent and subsequently esterifying the extracted compounds therein. SOLUTION: A benzyloxycarbonyl group is introduced into an amino group of an amino acid or its derivative in an aqueous medium and the resultant N-substituted amino acid is then extracted with an aromatic hydrocarbon solvent without isolation thereof from the aqueous medium. The extracted N-substituted amino acid is subsequently reacted with an alcohol in the presence of an acidic catalyst in the aromatic hydrocarbon solution to afford an N-carbobenzoxy- amino acid ester. Benzene, toluene, xylene, etc., are cited as the aromatic hydrocarbon and the toluene is especially preferred. Methanol is preferred as the alcohol and N-carbobenzoxy-S-phenyl-L-cysteine is preferred as the N-substituted amino acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an N-carbobenzoxyamino acid ester efficiently and at a high yield.

[0002]

2. Description of the Related Art A benzyloxycarbonyl group, also known as a Z group, is a typical amino group protecting group for amino acids and amino acid derivatives.
As a method for introducing a Z group into an amino acid or an amino acid derivative, benzyloxycarbonyl chloride (abbreviated as Z-Cl) is used, and the method is overwhelmingly performed by the Schotten-Baumann method. This method is carried out by dissolving an amino acid in an aqueous sodium hydroxide solution and dropping an equimolar amount of Z-Cl with the amino acid while maintaining alkalinity.

When the N-carbobenzoxyamino acid synthesized as described above is esterified with an alcohol to produce an N-carbobenzoxyamino acid ester, the above-mentioned alkaline aqueous solution of N-carbobenzoxyamino acid is treated with hydrochloric acid. Acidified with an acid such as
The carbobenzoxyamino acid is obtained by filtration, dried and subjected to the next esterification reaction. However, the crystallinity of N-carbobenzoxyamino acids is generally not good. If the stirring is weak, a large lumpy precipitate or an oily precipitate is deposited, and if the stirring is strong, the fine crystals become creamy in any case. Poor solid-liquid separation. Solid-liquid separation under strong acidity is not industrially preferable. Furthermore, the melting point of N-carbobenzoxyamino acids is often lower than 100 ° C., and drying is often difficult.

As a method for solving these problems, N
There is a method in which an alkaline aqueous solution of carbobenzoxyamino acid is acidified with an acid such as hydrochloric acid, and then N-carbobenzoxyamino acid is extracted with an organic solvent such as ethyl acetate. However, the next esterification reaction cannot be directly performed with an ester solvent such as ethyl acetate.

[0005]

Means for Solving the Problems In order to avoid the solid-liquid separation operation of N-carbobenzoxyamino acid having poor crystallinity, the present inventors have developed N-carbobenzoxy amino acid from an aqueous medium in which the amino group of the amino acid has been carbobenzoxylated. A study was conducted on a solvent capable of efficiently extracting N-carbobenzoxyamino acid without isolating the benzoxyamino acid and reacting with an alcohol in the solvent in the presence of an acid catalyst to produce an N-carbobenzoxyamino acid ester. As a result of the superposition, when N-carbobenzoxyamino acid is extracted using toluene, N-carbobenzoxyamino acid can be efficiently extracted, and the N-carbobenzoxyamino acid ester is reacted with alcohol in the solvent in the presence of an acid catalyst to form N-carbobenzoxyamino acid ester. They have found that they can be obtained in high yield and have completed the present invention.

That is, the present invention introduces a benzyloxycarbonyl group into an amino group of an amino acid or a derivative thereof in an aqueous medium in an aqueous medium, extracts the aromatic group without isolation from the aqueous medium, and then extracts the aromatic hydrocarbon. An object of the present invention is to provide a method for producing an N-carbobenzoxy amino acid ester, which is characterized by reacting with an alcohol in a hydrocarbon solution in the presence of an acid catalyst.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The amino acid as a raw material of the present invention is
Regardless of whether it is a natural product or a non-natural product, it may be a racemate, an optically active substance, a derivative thereof, or the like.

Examples of the amino-protecting group include protecting groups which are not deprotected under acidic conditions, such as nucleus-substituted or unsubstituted benzyloxycarbonyl groups.

The aromatic hydrocarbon used in the present invention includes, for example, benzene, toluene, xylene and the like.
Particularly, toluene is preferable.

The amount of the aromatic hydrocarbon used varies depending on the N-carbobenzoxy amino acid. For example, in the case of N-carbobenzoxy-S-phenyl-L-cysteine, 98% of the amount of toluene is about 7% of the weight of the aqueous layer. % Or more can be extracted. As described above, the N-carbobenzoxyamino acid can be concentrated by the extraction operation, and the esterification reaction can be efficiently performed.

The higher the extraction temperature, the better the extraction efficiency. However, it is preferable that the extraction is performed at a temperature lower than the azeotropic temperature at normal pressure of aromatic hydrocarbon and water, and at a temperature lower than 85 ° C. in the case of toluene.

The N-carbobenzoxyamino acid extracted with an aromatic hydrocarbon can be subjected to an esterification reaction by adding an acid catalyst to an aromatic hydrocarbon solution and then adding an alcohol.

At this time, when the aromatic hydrocarbon and water are azeotropic, the esterification reaction may be performed while performing azeotropic dehydration. In particular, when toluene is used, the reaction is carried out in a two-layer system of water and toluene. The esterification reaction can be carried out at a high yield without performing azeotropic dehydration.

The acid catalyst may be any as long as it catalyzes the esterification, and is generally a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or the like, or a solid acid catalyst such as strong cation exchange resin. Can be When the reaction is carried out using a two-layer reaction medium of water and an organic solvent that is hardly soluble in water, an acid containing water such as 35% hydrochloric acid can also be used. These acid catalysts can be used in combination of two or more.

Examples of the alcohol include methanol, ethanol, benzyl alcohol and the like, with methanol being particularly preferred.

After completion of the reaction, the aqueous layer is separated by a liquid separation operation, and if necessary, washing the solvent layer with water or an aqueous solution of a weak alkali salt, or dehydrating the solvent layer with a drying agent may be incorporated.

The isolation and purification of the N-substituted amino acid ester produced according to the present invention can be easily carried out according to known methods, for example, by concentration, recrystallization and the like.

[0018]

EXAMPLES The method of the present invention will be described below in detail with reference to examples. Example 1 6.6 g (33.5 mm) of S-phenyl-L-cysteine
ol) is suspended in 150 ml of water, and 3.3 g (37 mmol) of a 45% aqueous sodium hydroxide solution is added and dissolved. Under stirring, the temperature was maintained at ℃ C and 5.7 g of Z-Cl (3
(3.5 mol) is slowly added dropwise. To prevent the pH from dropping during the reaction, add 45% sodium hydroxide
H was kept at 11-12. After dropping Z-Cl, the mixture was stirred at the same temperature for about 1 hour to complete the reaction. After the completion of the reaction, an amount of toluene corresponding to 10% of the total weight of the reaction solution was added, and 35%
The pH was acidified with hydrochloric acid and extracted at 50 ° C. Generated N
Most of -carbobenzoxy-S-phenyl-L-cysteine was extracted into the toluene layer, and the concentration of N-carbobenzoxy-S-phenyl-L-cysteine in the toluene layer was 37.1%. The toluene layer was separated by liquid separation, and 5.2 g of 35% hydrochloric acid and 4.3 g of methanol were added to the toluene layer, and an esterification reaction was performed with stirring at 70 ° C. for 10 hours. Most of the generated N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester is present in the toluene layer, and the reaction yield is 98%.
Met.

Example 2 The procedure of Example 1 was followed except that the amount of toluene used was 30% of the total weight of the reaction solution. The reaction yield was 98%.

[0020]

According to the present invention, N-substituted amino acid esters can be efficiently produced in high yield without complicated solid-liquid separation operations or solvent substitution operations.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Nobuhiro Fukuhara 30 Asamuta-cho, Omuta-shi, Fukuoka Mitsui Toatsu Chemicals Co., Ltd.

Claims (4)

[Claims] 1. A benzyloxycarbonyl group is introduced into an amino group of an amino acid or a derivative thereof in an aqueous medium in an aqueous medium and extracted with an aromatic hydrocarbon without isolation from the aqueous medium. A method for producing an N-carbobenzoxyamino acid ester, characterized by reacting with an alcohol in the presence of an acid catalyst. 2. The method according to claim 1, wherein the aromatic hydrocarbon is toluene. 3. The method according to claim 1, wherein the alcohol is methanol. 4. The method according to claim 1, wherein the N-substituted amino acid is N-carbobenzoxy-S-phenyl-L-cysteine.
Or the production method according to 3.