JPH0347271B2 - - 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, by reacting the present compound with L-phenylalanine lower alkyl ester and then removing the protecting group carbobenzoxy group by hydrogenolysis, α-L-aspartyl-L-phenylalanine lower alkyl ester Alkyl esters can be obtained. This peptide has a sweet taste similar to sucrose, and 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 acid 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, the reaction temperature is 100°C or lower, minus 10°C or higher, preferably 80°C or lower, or higher than 0°C, from the viewpoint of suppressing racemization of the product as much as possible. The present inventor has conducted extensive research into 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, we have completed the present invention. The method of the present invention uses oxides, hydroxides, or salts of various metals with various acids, or aliphatic amines as a catalyst in the anhydration reaction to significantly increase the reaction rate. The target compound can be obtained quickly and in high yield. These metals include lithium, sodium, potassium (alkali metals), magnesium, calcium, etc. (alkaline earth metals), aluminum (borax), tin, lead (carbon group), manganese (manganese group), zinc (zinc group), etc. ), iron (iron group), and specific examples of one type of metal compound selected from these metals include oxides such as tin oxide and manganese dioxide, and water compounds such as sodium hydroxide and magnesium hydroxide. These include oxides, salts such as sodium carbonate, and sodium acetate. Aliphatic amines such as triethylamine and tributylamine are also effective. The amount used will vary somewhat depending on the type of compound added, but it is sufficient that it coexists 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 8, the amount of magnesium acetate added was 8x for N-carbobenzoxy-L-aspartic acid.
The weight ratio is 10 ^-6 (ie, 8 ppm), and it can be seen that even if such a small amount coexists, it exhibits an effective catalytic effect. Suitable amounts of these compounds to be present when the present invention is carried out industrially can be easily determined by those skilled in the art through preliminary experiments. In addition, the addition method is usually at the start of the anhydration reaction, but on the other hand, in the preparation method of the starting material N-carbobenzoxy-L-aspartic acid, the necessary amount of the above compound is attached to the crystal. This method is also quite effective. For example, N-carbobenzoxy-L-aspartic acid is crystallized and separated, but upon separation, it is washed with a dilute aqueous solution of the above compound,
It is also effective to attach it to crystals. As the solvent used in the present invention, any solvent can be used as long as it is not particularly active towards 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;
Halogenated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride, hydrocarbons such as toluene, xylene, hexane, cyclohexane, amides such as dimethylformamide, dimethyl sulfoxide, γ-butyrolactone, nitromethane, etc.; A typical example is a mixed solvent consisting of two or more arbitrary solvents. According to the method of the present invention, α-
The raw material compound N-carbobenzoxy-L-aspartic acid anhydride of L-aspartyl-L-phenylalanine lower alkyl ester can be obtained in a short time and in high yield. The present invention will be further explained below with reference to Examples. Example 1 N-carbobenzoxy-L-aspartic acid
80.2 g (0.30 mol) was suspended in 180 ml of toluene, the temperature was kept at 55°C while stirring, and 0.322 g (1.5 × 10 ^-3 mol) of magnesium acetate tetrahydrate and 33.7 g of acetic anhydride were suspended.
(0.33 mol) was added and the reaction was carried out for 3 hours. The resulting slurry was filtered under suction to obtain 68.0 g of crystals (isolated yield: 91%). The melting point and infrared absorption spectrum of this compound matched those of standard N-carbobenzoxy-L-aspartic anhydride. Incidentally, 10 ml of the slurry 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 diluted to 50 ml with methanol. When this was 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 that there is. 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 by the above analysis method, it was 100% after 3 hours.
It was hot. Comparative Example 1 After carrying out the reaction in Example 1 without adding magnesium acetate, 10 ml of the slurry was taken and analyzed by the above method, and the reaction yield was only 53.3%. Examples 2-21 Table 1 shows the results of adding various compounds. Conditions and operating methods other than those listed in Table 1 were carried out in the same manner as in Example 1.

【table】

[Table] Examples 22 to 23, 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 and acetic anhydride with Li, Na, Mg, Al, K, Ca, Mn,
N characterized by reacting in the presence of an oxide, hydroxide or salt of one metal selected from Fe, Zn, Sn and Pb or an aliphatic amine.
-Production method of carbobenzoxy-L-aspartic acid anhydride.