JPH05213925A - Production of n-benzyloxycarbonyl-l-aspartic acid anhydride - Google Patents

Abstract

PURPOSE:To produce Z-Asp-An on an industrial scale in high efficiency. CONSTITUTION:N-benzyloxycarbonyl-L-aspartic acid anhydride is produced by reacting N-benzyloxycarbonyl-L-aspartic acid with acetic anhydride in the presence of a solid acid catalyst. Z-L-Asp-An known as a raw material for alpha-APM useful as a sweetener can be produced in a short time in high yield.

Description

Detailed Description of the Invention

[0001]

The present invention relates to N-benzyloxycarbonyl-L-aspartic acid (hereinafter referred to as ZL-Asp).
Abbreviated) to its anhydride N-benzyloxycarbonyl-L-aspartic acid anhydride (hereinafter referred to as ZA).
abbreviated as sp-An).

The Z-Asp-An of the present invention is an important compound as an intermediate of α-L-aspartyl-L-phenyllanine methyl ester (hereinafter abbreviated as α-APM) used as a sweetener. .. For example, Japanese Patent Publication 57-
No. 25538, α-APM can be obtained by reacting Z-L-Asp-An with an L-phenylalanine lower alkyl ester and then removing the protecting group benzyloxycarbonyl by catalytic reduction. It is shown.

[0003] In particular, α-APM is widely known as a dipeptide-type sweetener, has high-quality sweetness characteristics and a sweetness degree nearly 200 times higher than that of sucrose, and the demand for it as a diet sweetener is greatly expanding. There is something.

[0004]

2. Description of the Related Art Conventionally, as a method for producing ZL-Asp-An, ZL-Asp was dissolved in a large excess of acetic anhydride, and acetic acid produced by reaction with excess acetic anhydride under reduced pressure was used. A method of obtaining ZL-Asp-An after distilling off and further removing an acetic acid by adding an organic solvent to the residue (Journal of American Chemical Society 81, 167-173 (1959)) Is known.

A method of obtaining a desired product by adding ZL-Asp as a slurry in acetic anhydride to a reaction at 50 ° C. or lower, and after cooling, adding a mixed liquid of ether and petroleum ether (Japanese Patent Laid-Open No. SHO 63-242242) 46-1370) or a method of reacting ZL-Asp with acetic anhydride in the presence of an aromatic hydrocarbon (JP-A-46-1370).

[0006]

In a conventionally known production example, acetic anhydride is used in a large excess, which is not economical, and in order to isolate the desired product, excess acetic anhydride and acetic acid are removed under reduced pressure. It has to be distilled off and the operation becomes complicated. Further, it is not a satisfactory method for industrial implementation such as adding an organic solvent having a low flash point.

Generally, when N-protected-L-aspartic acid anhydride is industrially produced, the N-protected-L-aspartic acid anhydride is not isolated but is then subjected to a condensation reaction with L-phenylalanine lower alkyl esters. It is desirable from the viewpoint of operation.

However, when the reaction is carried out using an excess amount of acetic anhydride as a dehydrating agent, N-acetyl-L-phenylalanine lower alkyl esters are produced in the subsequent condensation with L-phenylalanine lower alkyl esters. Therefore, there has been a demand for a production method in which the amount of acetic anhydride used is suppressed as much as possible and the reaction rate of anhydride conversion is increased.

As described above, the conventionally known ZL-Asp-A
Each of the manufacturing methods of n has its drawbacks, and is not always a satisfactory method as an industrial manufacturing method.

[0010]

The present inventors have found that Z-L-
In the method for producing Asp-An, the target compound Z which does not have the above-mentioned drawbacks of the conventional method and which can be produced in high yield and in a short time
As a result of extensive studies on a method for obtaining -L-Asp-An, in the present anhydride reaction, the addition of a solid acid catalyst markedly increased the reaction rate, and the target compound Z-L was obtained in a high yield in a short time.
The inventors have found that -Asp-An can be obtained, and completed the present invention.

That is, according to the present invention, N-benzyloxycarbonyl-L-aspartic acid is reacted with acetic anhydride in the presence of a solid acid catalyst to produce N-benzyloxycarbonyl-L-aspartic acid anhydride. Is the law.

Examples of the solid acid catalyst used in the present invention include activated clay, acid clay, silica alumina, silica magnesia, alumina boria and the like, and activated clay and acid clay are particularly preferable. The amount used is sufficient in the range of 1 to 30% by weight with respect to Z-L-Asp, and an appropriate amount of these catalysts to be present when the present invention is industrially carried out is preferably 1 to 10% by weight. ..

The solvent used in the present invention is
Acetone, ketones such as methyl ethyl ketone, diethyl ether, tetrahydrofuran, ethers such as dioxane, nitriles such as acetonitrile, ethyl acetate, esters such as methyl propionate, carboxylic acids such as formic acid, acetic acid and propionic acid, chloroform,
Halogenated hydrocarbons such as dichloromethane and ethylene dichloride, hydrocarbons such as toluene, xylene, hexane and cyclohexane, other amides such as dimethylformamide, dimethyl sulfoxide, γ-butyrolactone and nitromethane, and any of these. A mixed solvent consisting of two or more kinds is typical. However, from the viewpoint of solvent recovery, acetic acid solvent that is not necessary to be separated from acetic acid generated from the reaction is preferable.

The amount of acetic anhydride used in the present invention is preferably 0.5 mol ratio or more and 2 mol ratio or less with respect to ZL-Asp. Particularly preferably, the molar ratio is 0.9 or more and 1.05 or less. On the other hand, the reaction temperature is 100 ° C. or lower minus 10 from the viewpoint of suppressing racemization of the product.
C. or higher, preferably 80 ° C. or lower, 0 ° C. or higher.

As the reaction method, there can be used a method of adding a solid acid to cause a reaction and then removing the solid acid by filtration, or a method of filling the solid acid in a column or the like and circulating the reaction solution.

[0016]

EXAMPLES The method of the present invention will be described in detail below with reference to comparative examples and examples.

Comparative Example 67.0 g (0.25 mol) of ZL-Asp was added to acetic acid 12
Suspended in 9.4 g, acetic anhydride (purity 93%) 26.9 g
Was added and the reaction was carried out at a reaction temperature of 55 ° C. for 3 hours.
An appropriate amount of the obtained homogeneous reaction solution was taken and dissolved in a methanol solution containing 5% by weight of triethylamine.
Α- and β-N-benzyloxycarbonyl-L-aspartic acid methyl ester produced by the reaction of -L-Asp-An with methanol and the remaining ZL-Asp were quantified by high performance liquid chromatography. The reaction yield of ZL-Asp-an was calculated from the quantified value.

Example 1 67.0 g (0.25 mol) of ZL-Asp was added to acetic acid 12
Suspended in 9.4 g, acetic anhydride (purity 93%) 26.9 g
Was added, and 3.4 g of activated clay was added, and the reaction was carried out at a reaction temperature of 60 ° C. for 3 hours. Then, the activated clay was filtered, an appropriate amount of the filtrate was collected, and dissolved in a methanol solution containing 5% by weight of triethylamine. ZL-Asp-An
The α- and β-N-benzyloxycarbonyl-L-aspartic acid methyl ester and the remaining ZL-Asp were quantitatively determined by high performance liquid chromatography under the reaction of methanol with methanol. ZL-Asp from the quantified value
The reaction yield of -an was calculated.

Examples 2 to 6 The same procedure as in Example 1 was repeated except that the activated clay used in Example 1 was recycled.

Example 7 The procedure of Example 1 was repeated except that acid clay was used.

Examples 8 to 11 The procedure of Example 1 was repeated, except that the acid clay used in Example 7 was recycled.

Example 12 The same procedure as in Example 1 was carried out except that galeonite M-08 (manufactured by Mizusawa Chemical Co., Ltd.) was used in place of the activated clay and the reaction time was 8 hours.

Example 13 Example 13 was repeated except that Shilton DR-1 (manufactured by Mizusawa Chemical Co., Ltd.) was used in place of the activated clay.
The results of Comparative Examples and Examples 1 to 13 are shown in Table-1 (Tables 1 and 2).
Shown in.

[0024]

[Table 1]

[0025]

[Table 2]

[0026]

INDUSTRIAL APPLICABILITY According to the present invention, ZL-Asp-An, which is a raw material compound of the sweetener α-APM, can be obtained in a short time in a high yield.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI technical display location // C07B 61/00 300 (72) Inventor Akihiro Yamaguchi 1190 Kasamacho, Sakae-ku, Yokohama, Kanagawa Pressure Chemical Co., Ltd.

Claims (3)

[Claims] 1. N-benzyloxycarbonyl-L-aspartic acid and acetic anhydride are reacted in the presence of a solid acid catalyst.
A method for producing L-aspartic anhydride. 2. The N-benzyloxycarbonyl-L- according to claim 1, wherein the solid acid catalyst is activated clay, acid clay, silica alumina, silica magnesia, or alumina boria.
Method for producing aspartic anhydride. 3. The N-benzyloxycarbonyl-L according to claim 1, wherein the solid acid catalyst is reused.
-Method for producing aspartic anhydride.