JPH05320151A - Production of n-benzyloxycarbonyl-l-aspartic acid anhydride - Google Patents

Abstract

PURPOSE:To obtain an N-benzyloxycarbonyl-L-aspartic acid anhydride in high yield and quality in a short time by reacting N-benzyloxycarbonyl-L-aspartic acid with acetic anhydride in the presence of a metal alkoxide. CONSTITUTION:This compound is produced by reacting N-benzyloxycarbonyl-L- aspartic acid (ZASP) with acetic anhydride in the presence of a metal alkoxide catalyst (e.g. titanium tetraisopropoxide) in a solvent (e.g. acetone) at 20-100 deg.C. The amount of the acetic anhydride is 0.9-1.1mol based on 1mol of ZASP and that of the catalyst is 0.001-10mol% based on ZASP. The reaction goes to completion usually within 10hr. The compound is useful as an intermediate for peptide synthesis, especially as a raw material for N-benzyloxycarbonyl-alpha-L- aspartyl-L-phenylalanine methyl ester.

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.

As a result, when ZASP is anhydrateized with acetic anhydride, a metal alkoxide is found as a novel catalyst suitable for the purpose, and a substantially theoretical amount or a near amount thereof is used in a short time with a high yield. ZASP anhydride can be produced, and further, the yield of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester obtained by reacting ZASP anhydride with L-phenylalanine methyl ester without isolation ,
The inventors have found that there is no problem with quality and have completed the present invention.

That is, the present invention is a method for producing ZASP anhydride from ZASP and acetic anhydride, which comprises reacting ZASP and acetic anhydride in the presence of various metal alkoxides. is there.

The method of the present invention is a method for producing ZASP anhydride from ZASP and acetic anhydride, and a high yield of ZASP anhydride is obtained in a short time by using acetic anhydride in a substantially theoretical amount or in the vicinity 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, a catalytic amount of a metal alkoxide is used in the production of ZASP anhydride by reacting ZASP with acetic anhydride. Specific examples of the metal alkoxide used include periodic table 2A elements such as magnesium and calcium, 3B group elements such as scandium, 4B group elements such as titanium and zirconium, 5B group elements such as vanadium, chromium, 6B element such as molybdenum,
7B group elements such as manganese, 8B group elements such as iron, cobalt and nickel, 1B group elements such as copper, 2B group elements such as zinc, 3A group elements such as aluminum, 4 such as silicon and tin
It is a metal alkoxide made of various metals such as Group A elements and Group 5A elements such as phosphorus. In addition, as alkyl groups of these metal alkoxides, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, se
c-pentyl, tert-pentyl, neopentyl,
Alkyl groups such as 1,2-dimethylpropyl, isohexyl, n-hexyl, sec-hexyl, tert-hexyl and cyclohexyl are effective.

The amount of the metal alkoxide used is usually a catalytic amount. However, if the amount is too small, the catalytic effect will be small, and if the amount is too large, it is not economically preferable. Usually ZA
0.001 to 10 mol% with respect to SP, preferably 0.1.
It is used in the range of 005 to 5 mol%. Suitable amounts of these compounds to be present when the present invention is industrially carried out are
Those skilled in the art can easily find out by preliminary experiments. Further, the addition method is generally added at the start of the anhydride reaction, but in practice, there is no problem as long as the metal alkoxide is present in the reaction system during the reaction.

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
-Benzyloxycarbonyl-α-L-aspartyl-
This is not preferable because it causes a decrease in the yield of L-phenylalanine methyl ester.

The method of the present invention will be described in detail. For example, a predetermined amount of metal alkoxide is added to an organic solvent solution in which ZASP is dissolved or suspended, and then a predetermined amount of acetic anhydride is charged to carry out the reaction. The method of making it possible can be 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-benzyloxycarbonyl-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.

[0018]

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 26.8 g (0.100 mol) of ZASP was dissolved in 52 g of acetic acid, the temperature was kept at 60 ° C. with stirring, and 0.93 g (0.0033 mol) of titanium tetraisopropoxide and 10. 9 g (0.107 mol) was added and reacted for 1 hour. As a result of analyzing a part of the obtained solution by HPLC, ZASP anhydrous was obtained in a purity conversion yield of 96.5%.

Example 2 Titanium tetraisopropoxide 0.09 g (0.000)
(3 mol) was carried out in the same manner as in Example 1 to obtain ZASP anhydride in a purity conversion yield of 97.2%.

Example 3 As a metal alkoxide, magnesium diethoxide.
When 35 g (0.0031 mol) was used and carried out in the same manner as in Example 1, ZASP anhydride was obtained in a purity conversion yield of 96.8%.

Comparative Example When the reaction was performed in the same manner as in Example 1 without adding a metal alkoxide as a catalyst, ZASP anhydride was obtained in a purity conversion yield of 32.6%.

[0023]

INDUSTRIAL APPLICABILITY The method of the present invention always produces ZASP with high yield.
It is an industrially extremely useful 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. 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 a metal alkoxide. 2. The method according to claim 1, wherein a metal alkoxide having an alkyl group having 1 to 6 carbon atoms is used.