JPH05331160A - Production of n-benzyloxycarbonyl-l-asparticl acid anhydride - Google Patents

Abstract

PURPOSE:To improve the productivity of the objective N-benzyloxycarbonyl-L- aspartic acid anhydride and produce the compound in high yield and quality in a short time. CONSTITUTION:N-benzyloxycarbonyl-L-aspartic acid anhydride is produced by reacting N-benzyloxycarbonyl-L-aspartic acid with acetic anhydride in the presence of an aliphatic or aromatic sulfonic acid ammonium salt.

Description

Detailed Description of the Invention

[0001]

The present invention relates to N-benzyloxycarbonyl-L-aspartic acid which is an anhydride of N-benzyloxycarbonyl-L-aspartic acid.
-A method for producing benzyloxycarbonyl-L-aspartic anhydride.

[0002]

The object compound of the present invention N-benzyloxycarbonyl-L-aspartic acid anhydride (hereinafter referred to as ZASP)
Abbreviated as anhydrous. ) Is an important compound as an intermediate during peptide synthesis. Particularly, in recent years, the demand for α- has been remarkably increased due to its high degree of sweetness and high-quality sweetness characteristics.
It is an important compound as an intermediate in the production of L-aspartyl-L-phenylalanine methyl ester (aspartame).

Various methods have been disclosed so far for producing the α-L-aspartyl-L-phenylalanine methyl ester. Generally, N-protected aspartic anhydride and L-phenylalanine methyl ester are reacted to form N-protected α-L-aspartyl-
The method of producing L-phenylalanine methyl ester and subsequently removing the N-protecting group is suitable as an industrial production method. However, since α-L-aspartyl-L-phenylalanine methyl ester is a compound that is unstable to heat, acid, and alkali, the N-protecting group of N-protected α-L-aspartyl-L-phenylalanine methyl ester is removed. The separation step is naturally limited, and it is desirable that the separation step can be performed under neutral and mild conditions. In that sense, a benzyloxycarbonyl group that can be eliminated by a hydrogenation reaction is an industrially suitable N-protecting group, and α-L-aspartyl-L-phenylalanine methyl ester using this protecting group Various improved manufacturing methods have been proposed.

Conventionally, there is known a method for producing ZASP anhydride by reacting N-benzyloxycarbonyl-L-aspartic acid (hereinafter abbreviated as ZASP) with acetic anhydride in a solvent or without solvent. In the old days, it was heated to react with a large excess of acetic anhydride to form an anhydride, and then the excess acetic anhydride was distilled off, and a solvent such as petroleum ether was added, and ZA was added.
The SP anhydride was isolated as crystals and used in the next step. However, such a method complicates the operation and further causes a loss to the mother liquor during isolation, so that it is not necessarily an industrial production method. Industrially, it is desirable to directly react the reaction solution with L-phenylalanine methyl ester without isolating ZASP anhydride.
However, if a large amount of acetic anhydride remains after the ZASP is anhydridized, the reaction yield with the subsequent L-phenylalanine methyl ester will decrease, which is not preferable. In this method, it is necessary to devise a method in which acetic anhydride used as an anhydride-forming agent is hardly left in the reaction solution after the anhydride, and for that purpose, the theoretical amount of acetic anhydride is used as much as possible, and the yield is high. It is necessary to produce ZASP anhydride.

The method for producing ZASP anhydride by reacting ZASP with a theoretical amount of acetic anhydride requires a long reaction time until the reaction is completed even if this anhydride reaction is carried out in a homogeneous system in acetic acid. And On the other hand, if the reaction temperature is increased to shorten the reaction time, ZASP and ZASP
It is not preferable because the anhydride decomposes, resulting in a decrease in reaction yield.

Several catalysts have been proposed so far as a method for increasing the reaction rate of ZASP anhydride reaction and producing ZASP anhydride in a high yield. One is a method which is carried out in the presence of an acid catalyst having a dissociation constant of 5 × 10 ^-2 or more as seen in JP-A-58-167578, and the other is a metal oxide disclosed in JP-A-58-167577. -This method is carried out in the presence of a hydroxide / salt or an organic base catalyst. In fact, the catalysts described in these prior art are found to be effective as catalysts for this dehydration reaction.

[0007]

The present inventor believes that it is necessary to find an industrially more useful process for producing ZASP anhydride in addition to these conventionally known techniques, and ZASP and acetic anhydride are used to produce ZASP anhydride. In the method for producing (1), the inventors have earnestly studied a method for further improving the productivity and producing the desired ZASP anhydride in a high yield and high quality in a short time.

[0008] As a result, when ZASP is anhydrated with acetic anhydride, various aliphatic or aromatic ammonium sulfonates or ammonium sulfamate are found as novel catalysts suitable for the purpose, and the theoretical amount or a near amount thereof is practically used. It was found that ZASP-anhydride can be produced in high yield in a short time with acetic anhydride, and at the same time, the ZASP-anhydride is reacted with L-phenylalanine methyl ester without isolation to obtain N-benzyloxylvonyl-
The inventors have found that there is no problem in the yield and quality of α-L-aspartyl-L-phenylalanine methyl ester, and have completed the present invention.

That is, according to the present invention, in a method for producing ZASP anhydride from ZASP and acetic anhydride, ZASP and acetic anhydride are reacted in the presence of various aliphatic or aromatic ammonium sulfonates or ammonium sulfamate. It is a characteristic method for producing ZASP anhydride.

The method of the present invention is a method for producing ZASP anhydride from ZASP and acetic anhydride, and a substantially high yield of ZASP anhydride is obtained in a short time by using a stoichiometric amount of acetic anhydride or a theoretical amount thereof. ZA for the purpose of manufacturing
This is a method for producing SP anhydrous.

The present invention is usually practiced in organic solvents. The solvent used is not particularly limited as long as it is inert to the raw materials and products. Specifically, 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. Acids, halogenated hydrocarbons such as chloroform, dichloromethane and ethylene dichloride, hydrocarbons such as toluene, xylene, hexane and cyclohexane, amides such as dimethylformamide, dimethyl sulfoxide,
Examples include γ-butyrolactone and nitromethane. These solvents are usually used alone, but
There is no problem in using more than one solvent together.

In the present invention, when acetic anhydride is allowed to act on ZASP to produce ZASP anhydride, a catalytic amount of ammonium ammonium aliphatic or aromatic or ammonium sulfamate is used. Specific examples of the aliphatic or aromatic ammonium sulfonates used include ammonium methanesulfonate, ammonium ethanesulfonate, ammonium 1- and 2-propanesulfonate, ammonium 1- and 2-butanesulfonate,
Ammonium pentane sulfonate, ammonium trifluoromethane sulfonate, ammonium trichloromethane sulfonate, ammonium benzyl sulfonate, ammonium nitrobenzene sulfonate, ammonium P-toluene sulfonate, ammonium chlorobenzene sulfonate, ammonium dichlorobenzene sulfonate, bromobenzene sulfonate Examples thereof include ammonium, ammonium nitrobenzenesulfonate, ammonium naphthalenesulfonate, and ammonium naphthalenedisulfonate.

The amount of the aliphatic or aromatic ammonium sulfonate or ammonium sulfamate used may be usually a catalytic amount, but if it is too small, the catalytic effect will be small, and if it is too large, it is not economically preferable. Usually Z
It is used in the range of 0.001 to 10 mol%, preferably 0.005 to 5 mol% based on ASP. Appropriate amounts of these compounds to be present when the present invention is industrially carried out can be easily found by those skilled in the art by preliminary preliminary experiments. In addition, the addition method is generally added at the start of the anhydride reaction, but in practice, the form should be such that an aliphatic or aromatic ammonium sulfonate or ammonium sulfamate is present in the reaction system during the reaction. If there is no problem.

In the method of the present invention, the amount of acetic anhydride used is in the range of 0.9 to 1.1 mol ratio, preferably 0.95 to 1.05 mol ratio, based on ZASP. Even if acetic anhydride is used in a remarkably excessive amount relative to ZASP, there is no particular problem only in the ZASP anhydride reaction. However, since this reaction solution is directly used in the reaction with L-phenylalanine methyl ester, excess acetic anhydride is used. Existence is N
-Benzyloxylvonyl-α-L-aspartyl-L
-It is not preferable because the yield of phenylalanine methyl ester is reduced.

The specific method of carrying out the method of the present invention is as follows. For example, a predetermined amount of ammonium or aliphatic or aromatic ammonium sulfonate or ammonium sulfamate is added to an organic solvent solution in which ZASP is dissolved or suspended. A method in which a fixed amount of acetic anhydride is charged and reacted is mentioned. However, the order of charging the raw materials is not limited to this, and any order may be used.

If the reaction temperature is too low, the reaction rate is slow, and if it is too high, the reaction rate remarkably increases.
The decomposition reaction of SP and ZASP anhydride occurs, and conversely Z
Since the yield and quality of ASP anhydrous are deteriorated, 20
The range of -100 ° C, preferably 30-80 ° C is good.

The reaction time is not uniquely determined by the amount of catalyst and the reaction temperature, but usually the reaction is completed within 10 hours and ZASP anhydride is obtained in high yield.

Thus, according to the method of the present invention, ZASP anhydride, which is a raw material of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester, which is extremely useful industrially, is converted into N-benzyloxylvonyl-L. It can be obtained from aspartic acid in a short time and in high yield. Moreover, the obtained ZASP anhydride can be directly reacted with the following L-phenylalanine methyl ester without being isolated from the reaction system. Therefore, it is an industrially extremely valuable method for producing ZASP anhydride.

[0019]

EXAMPLES The present invention will be further described below with reference to examples, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded. The ZASP anhydride was quantified by HPLC internal standard method by adding aniline to the reaction solution to give anilide.

Example 1 ZASP (26.7 g, 0.100 mol) was dissolved in acetic acid (52 g), the temperature was maintained at 60 ° C. with stirring, and ammonium trifluoromethanesulfonate (0.50 g, 0.0030 mol) and acetic anhydride (10) were added. 0.5 g (0.103 mol) was added and the reaction was carried out for 2 hours. Part of the obtained solution is HPL
As a result of analysis by C, the yield of ZASP anhydride was 9 in terms of purity.
Obtained at 5.2%.

Example 2 0.05 g of ammonium trifluoromethanesulfonate
(0.0003 mol) was carried out in the same manner as in Example 1 to obtain ZASP anhydride in a purity conversion yield of 93.2%.

Example 3 Ammonium benzenesulfonate 0.53 g (0.00
30 mol) and the same procedure as in Example 1 is performed to obtain ZASP.
An anhydride was obtained in a purity conversion yield of 94.2%.

Example 4 0.34 g (0.0030) of ammonium sulfamate
Mol) was carried out in the same manner as in Example 1 to obtain ZASP anhydride in a purity conversion yield of 95.4%.

Comparative Example When the reaction was carried out in the same manner as in Example 1 without adding a catalyst, ZA was obtained.
SP anhydrous was obtained in a purity conversion yield of 60.2%.

[0025]

INDUSTRIAL APPLICABILITY The method of the present invention always produces ZASP with high yield.
It can be said that this method is industrially extremely useful as a method for obtaining an anhydride.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Ryuichi Mita 30 Asamuta-cho, Omuta-shi, Fukuoka Mitsui Toatsu Chemical Co., Ltd.

Claims (2)

[Claims] 1. N-benzyloxycarbonyl-L-aspartic acid and acetic anhydride are reacted in the presence of an aliphatic or aromatic ammonium sulfonate.
-A method for producing benzyloxycarbonyl-L-aspartic anhydride. 2. A method for producing N-benzyloxycarbonyl-L-aspartic acid anhydride, which comprises reacting N-benzyloxycarbonyl-L-aspartic acid with acetic anhydride in the presence of ammonium sulfamate.