JPH0314029B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing N-carbobenzoxy-L-aspartic acid anhydride from N-carbobenzoxy-L-aspartic acid. Target compound of the present invention N-carbobenzoxy-L
-Aspartic anhydride is important as a peptide synthesis intermediate. For example, after reacting the present compound with L-phenylalanine lower alkyl ester, the protecting group carbobenzoxy group is removed by hydrogenolysis, thereby reducing α-L-aspartyl-L-phenylalanine lower alkyl ester. Alkyl esters can be obtained. In addition, this peptide has a sweet taste similar to sucrose,
It is a substance that is attracting attention as a new sweetener. In the production of N-carbobenzoxy-L-aspartic acid anhydride, N-carbobenzoxy-
By dissolving or suspending L-aspartic acid in a solvent and allowing a dehydrating agent to act, a solution or suspension of N-carbobenzoxy-L-aspartic acid anhydride can be obtained. Industrially, it is desirable to react the produced N-carbobenzoxy-L-aspartic anhydride with L-phenylalanine lower alkyl ester as a solution or suspension without isolating it. As the dehydrating agent used in this reaction, it is preferable to use acetic anhydride, which does not produce by-products that adversely affect subsequent steps. Furthermore, it is also undesirable that a large amount of acetic anhydride remains in the reaction-completed solution, considering the influence on subsequent steps. From this, the appropriate amount of acetic anhydride is:
The amount used is 0.7 to 1.3 times the mole of raw material N-carbobenzoxy-L-aspartic acid. On the other hand, from the viewpoint of suppressing racemization of the product as much as possible, the reaction temperature is 100°C or lower, minus 10°C or higher, preferably 80°C or lower and 0°C or higher. The present inventor has worked hard to develop a method for obtaining the target compound N-carbobenzoxy-L-aspartic acid anhydride in a high yield and within a practically sufficient reaction time under the above-mentioned restricted conditions. As a result of our studies, we have completed the present invention. The method of the present invention uses an acid as a catalyst in the anhydration reaction to significantly increase the reaction rate and obtain the target compound in high yield. is 5×10 ^-2
The above acids, such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, inorganic acids such as perchloric acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, trichloroacetic acid, trifluoroacetic acid, various carboxylic acids, etc. It is an organic acid. The amount used varies somewhat depending on the type of acid to be added, but it is sufficient to coexist in a small amount, and it can be suppressed to the extent that it does not affect the subsequent process. For example, as shown in Example 3, the amount of sulfuric acid added is N-carbobenzoxy-
The weight ratio of L-aspartic acid to L-aspartic acid is 7 x 10 ^-3 , and it can be seen that even if such a small amount coexists, it exhibits an effective catalytic action. The appropriate amount of acid to be present when carrying out the present invention industrially can be easily found by those skilled in the art through preliminary experiments. The acid is usually added at the start of the anhydration reaction, but the method for preparing the starting material N-carbobenzoxy-L-aspartic acid is devised so that the necessary amount of acid is attached to the crystals. The method is also quite effective. For example, N-carbobenzoxy-L
- Aspartic acid is crystallized and separated, but it is also effective to replace the crystal adhering liquid with a dilute aqueous acid solution during separation, and use the crystals adhering to the acid as a starting material. Any solution can be used in the present invention as long as it is not particularly active against the reactants and products. Ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, tetrahydrofuran and 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 and dichloromethane. , halogenated hydrocarbons such as ethylene dichloride, hydrocarbons such as toluene, xylene, hexane, and cyclohexane, other amides such as dimethylformacide, dimethyl sulfoxide, γ-butyrolactone, nitromethane, etc., and any of these. A typical example is a mixed solvent consisting of two or more types. According to the present invention, α-L-
Raw material compound N-carbobenzoxy- of aspartyl-L-phenylalanine lower alkyl ester
L-aspartic acid anhydride can be obtained in a short time and in high yield. The present invention will be further explained using Examples. Example 1 N-carbobenzoxy-L-aspartic acid
Suspend 80.2g (0.30mol) in 180ml of toluene,
Keep the stirring temperature at 55℃ and add 0.15g of 98% sulfuric acid.
(0.0015 mol) and 33.7 g (0.33 mol) of acetic anhydride were added, and the reaction was carried out for 3 hours. The obtained slurry was filtered by absorption to obtain 66.8g of crystals.
(isolated yield 89%). The melting point and infrared absorption spectrum of this compound were consistent with that of standard l-carbobenzoxy-L-aspartic acid anhydride. Incidentally, 10 ml of the slurry liquid obtained by repeating the same reaction was taken, dissolved in an appropriate amount of methanol solution containing 5% by volume of triethylamine, concentrated under reduced pressure to remove toluene, and then diluted to 50 ml with methanol. When diluted and analyzed by high performance liquid chromatography (Hitachi 635A, column packing material: Hitachi Gel #3011-0), three main peaks were observed. Identification from standard samples revealed that they were N-carbobenzoxy-L-aspartic acid, N-carbobenzoxy-L-aspartic acid-α-methyl ester, and N-carbobenzoxy-L-aspartic acid-β-methyl ester. I confirmed something. This is because N-carbobenzoxy-L-aspartic acid anhydride interacted with methanol to produce α and β methyl ester compounds.
Conversely, by quantifying these ester compounds, the content of N-carbobenzoxy-L-aspartic anhydride can be determined. Hereinafter, the reaction yield was determined by such a method. Incidentally, when the reaction yield in Example 1 was measured using the above analysis method, it was found that after 3 hours, 100
It was %. Comparative Example 1 After carrying out the reaction in Example 1 without adding sulfuric acid, 10 ml of the slurry was taken and analyzed by the above method, and the reaction yield was only 53.3%. Examples 2 to 10 Table 1 shows the results of adding various compounds. Conditions and operating methods other than those listed in Table 1 were the same as in Example 1.

[Table] Examples 11-12, Comparative Example 2 Table 2 shows the results of experiments conducted at different reaction temperatures. Other conditions and operating methods were the same as in Example 1.

【table】

Claims (1)

[Claims] 1 N-carbobenzoxy-L-aspartic acid anhydride, characterized in that N-carbobenzoxy-L-aspartic acid and acetic anhydride are reacted in the presence of an acid having a dissociation constant of 5 x 10 ^-2 or more. manufacturing method.