JP2788496B2 - Method for producing N-carbobenzoquine-L-aspartic anhydride - Google Patents

Description

The present invention relates to N-carbobenzoxy-L-aspartic acid (hereinafter abbreviated as ZL-Asp). Acid anhydride (hereinafter, ZL-
(Abbreviated as AspAn).

Z-L-AspAn is α-L- used as a sweetener.
It is an important compound as an intermediate of aspartyl-L-phenylalanine lower alkyl ester (hereinafter abbreviated as α-APE). For example, Japanese Patent Publication No. 57-25538 discloses that after reacting Z-L-AspAn with a lower alkyl ester of L-phenylalanine, the carbobenzoxy group as a protecting group is eliminated by catalytic reduction to obtain α-. AP
It is shown that E is obtained.

In particular, α-L which is a methyl ester in α-APE
-Aspartyl-L-phenylalanine methyl ester is widely known as a dipeptide-based sweetener, has good sweetness characteristics and a high sweetness nearly 200 times higher than that of sucrose, and its demand as a diet sweetener has greatly increased. Is what it is.

[Conventional technology and problems to be solved]

Conventionally, ZL has been used as a method for producing ZL-AspAn.
-Asp is dissolved in a large excess of acetic anhydride, the acetic acid generated by the reaction with the excess acetic anhydride is distilled off under reduced pressure, and an organic solvent is added to the residue to remove the remaining acetic acid. -Method for obtaining L-AspAn (Journal of American Chemical Society 81 , 167-173 (195
9) is known.

Also, a method is disclosed in which a slurry is prepared from ZL-Asp in acetic anhydride, the reaction is carried out at 50 ° C. or lower, and after cooling, a mixture of ether and petroleum ether is added to obtain the desired product (Japanese Patent Application Laid-Open No. 46-1370). ) Or a method in which the reaction between ZL-Asp and acetic anhydride is carried out in the presence of an aromatic hydrocarbon (JP-A-48-75542).

However, in any of the methods, acetic anhydride is used in a large excess, which is not economical.In addition, excess acetic anhydride and acetic acid are distilled off under reduced pressure to isolate the target substance, or flash is used to reduce the solubility. It was not a satisfactory method for industrial implementation, such as the necessity of adding an organic solvent having a low point.

Generally, when N-protected-L-aspartic anhydride is industrially produced, it is possible to carry out a condensation reaction with L-phenylalanine lower alkyl esters without isolating the N-protected-L-aspartic anhydride. Operationally desirable.

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

JP-A-58-167577 discloses a method in which a reaction between ZL-Asp and acetic anhydride is carried out in the presence of an oxide, hydroxide or salt of various metals or an organic base compound.

In the above method, a third substance other than a raw material, a product, a solvent, and acetic anhydride is added. Therefore, there is a possibility of affecting the subsequent process, and it is necessary to consider the influence.

As described above, the conventionally known methods for producing ZL-AspAn have disadvantages, and are not always satisfactory methods for industrial production.

[Means for solving the problem]

The present inventors have intensively studied a method for obtaining the target compound ZL-AspAn in a method for producing ZL-AspAn which does not have the above-mentioned disadvantages of the conventional method in a method for producing ZL-AspAn, and which has a high yield and a short time. As a result, in this anhydride conversion reaction, ZL-AspA
It has been found that the addition of n significantly increases the reaction rate, and that the desired compound ZL-AspAn can be obtained in a short time and with high yield, thus completing the present invention.

That is, the present invention is characterized in that N-carbobenzoxy-L-aspartic acid and acetic anhydride are reacted in the presence of ZL-AspAn.
This is a method for producing aspartic anhydride.

The amount of ZL-AspAn to be added in advance slightly varies depending on the type of the solvent, but it is sufficient that a small amount coexist. For example, as shown in Example 3, the amount of Z-AspAn added is Z-AspAn.
It is 0.1% by weight with respect to L-Asp, and it can be seen that an effective catalytic action is exhibited even in such a small amount. The amount of this compound present when the present invention is practiced industrially is
It is sufficient that the content is 0.01% or more, preferably 0.1% or more in terms of% by weight with respect to ZL-Asp, and there is no particular upper limit.

In addition, as an addition method, in addition to adding Z-AspAn in a solid state, adding it by dissolving or suspending it in a solvent, or leaving a part of the reaction mass of anhydride of ZL-Asp as it is Or by various addition methods. That is, the difference in the addition method does not impair the essence of the present invention, and any addition method is possible.

As the solvent used in the present invention, any solvent can be used unless it is particularly active in reactants and products. Acetone, ketones such as methyl ethyl ketone, ethers such as diethyl ether, tetrahydrofuran, dioxane, nitriles such as acetonitrile, esters such as ethyl acetate and methyl propionate, carboxylic acids such as formic acid, acetic acid and propionic acid,
Chloroform, dichloromethane, halogenated hydrocarbons such as ethylene dichloride, toluene, xylene, hexane, hydrocarbons such as cyclohexane, amides such as dimethylformamide, dimethyl sulfoxide, γ-butyrolactone, nitromethane, and the like A mixture of two or more arbitrary solvents is typical.

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

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples.

Example 1 ZL-Asp 67.0 g (0.25 mol) and ZL-AspAn 0.67 g
(2.69 × 10 −3 mol) was suspended in 129.4 g of toluene, 26.9 g of acetic anhydride (purity 93%) was added, and the reaction was carried out at a reaction temperature of 55 ° C. for 3 hours. An appropriate amount was taken from the obtained reaction solution, dissolved in a methanol solution containing 5% by weight of triethylamine, and N-carbobenzoxy-L-aspartic acid of α and β generated by the reaction of ZL-AspAn with methanol The methyl ester and the remaining ZL-Asp were quantified by high performance liquid chromatography. The reaction yield of ZL-AspAn was calculated from the quantified value.

Reaction yield 92.6% Comparative example ZL-Asp 67.0 g (0.25 mol) was suspended in toluene 129.4 g, and acetic anhydride (purity 93%) 26.9 g was added.
The reaction was performed at 5 ° C. for 3 hours. An appropriate amount was taken from the obtained reaction solution, dissolved in a methanol solution containing 5% by weight of triethylamine, and N-carbobenzoxy-L-aspartic acid of α and β generated by the reaction of ZL-AspAn with methanol Methyl ester and remaining ZL
-Asp was quantified by high performance liquid chromatography. The reaction yield of ZL-AspAn was calculated from the quantified value.

Reaction yield 42.3% Examples 2 to 5 The reaction conditions were the same as in Example 1 except for changing the solvent.

Examples 6 to 7 The reaction conditions were the same as in Example 1 except that the amount of acetic anhydride was changed.

Examples 8 to 10 The reaction conditions were the same as in Example 1 except for the amount of Z-AspAn added in advance.

 Table 1 shows the results of Examples 2 to 10.

[Effects of the Invention] According to the present invention, raw materials, products, solvents, without adding a third substance other than acetic anhydride, an industrially useful α
It is possible to obtain ZL-AspAn, which is a starting compound of -APE, in a short time and at a high yield.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 307/66 C07K 5/06-5/078

Claims (1)

(57) [Claims] (1) N-carbobenzoxy-L-aspartic acid is reacted with acetic anhydride in the presence of N-carbobenzoxy-L-aspartic anhydride.
-A method for producing carbobenzoxy-L-aspartic anhydride.