JPS604810B2 - Method for producing dibasic acidic amino acid ω-monoester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing monoesters of dibasic acidic amino acids represented by the general formula.

In the above formula, R represents an alkyl group, cycloalkyl group, aralkyl group, or aryl group having 10 or less carbon atoms, and n represents 1 or 2.

In the general formula '11, R is preferably a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and rt-butyl, or cyclobentyl or cyclohexyl.

Indicates an alkyl group, an aralkyl group such as benzyl or phenethyl, or an aryl group such as phenyl. A particularly preferred compound is one in which R is a lower alkyl group and n is 1 to 2.
Examples include compounds that are . The present invention relates to optically active or inactive general formulas (where n has the same meaning as described above).

) in alcohol,
A general formula obtained by esterification by adding an equivalent amount or a small excess of hydrochloric acid (wherein R and n have the same meanings as described above).

) to a reaction solution of ester hydrochloride represented by the general formula (wherein R' and R'' represent hydrogen, a lower alkyl group, or a halogenoalkyl group, preferably R' is hydrogen and R'' is a methyl group or chloromethyl group). Indicates the group.

) to form a compound (m).
This is a method for producing a monoester of a dibasic acidic amino acid, which comprises treating hydrochloric acid to obtain a monoester of a free amino acid represented by the general formula (1). The purpose of the method of the present invention is to produce synthetic polypeptides in the fields of resins and fibers, medicines, etc.
This is useful in the free form of dibasic acidic amino acids.
The objective is to industrially produce monoester with high quality, high yield, and ease.

Conventionally, the method for producing a monoester of a dibasic acidic amino acid involves reacting an amino acid with an alcohol in the presence of an equivalent amount or a slight excess of an acidic substance relative to the amino acid, and then reacting with sodium hydroxide, potassium hydroxide or A method of neutralizing acidic substances by adding an alkali metal hydroxide, alkali metal carbonate, or ammonia such as potassium carbonate or sodium bicarbonate (West German Published Patent Application No. 2,158,5
62: U.S. Patent No. 3,770,807) or neutralize by adding an organic amine such as pyridine or triethylamine,
Method for isolating free amino acid Yamaichi monoester by precipitation (Japanese published patent No. 391-6656; Metod
yPoluch. Khim. Reaktiv. Prep
．． 1970, No. 22, 50-5), and a method of isolation by contacting the ester reaction solution with a weakly basic anion exchange resin (Japanese Patent Publication No. 41-6263). However, when industrially producing monoesters of dibasic acidic amino acids, these methods have the following disadvantages. In the method of neutralizing acidic substances with alkali metal hydroxides, alkali metal carbonates, ammonia, organic amines, etc., the salts produced by neutralization mix with the monoester of the amino acid, resulting in a decrease in quality. bring. This poses a serious problem, particularly in polymerization reactions in which monoesters of dibasic acidic amino acids are mainly used. It is not easy to separate and remove these salts from the monoester of the amino acid, and it is necessary to recrystallize the monoester of the amino acid,
Alternatively, a so-called purification step is required, in which the crystals are washed with a large amount of solvent, and furthermore, such an operation lowers the yield of the monoester of the amino acid, resulting in an economic disadvantage. In particular, it is necessary to recover organic amines for economic reasons, and to isolate and recover these amines from the alcoholic solution after isolating the monoester of the amino acid, it requires complicated operations, a huge amount of equipment, and a large amount of equipment. requires a lot of time and effort. {In the method of removing acidic substances from the ester reaction solution using an ion exchange resin, there is a step of concentrating the dilution water used during contact with the ion exchange resin and a large amount of water used for washing the resin. Because it is crystallized and isolated from an aqueous solution, a drop in yield is seen due to the solubility of amino acid monoesters, and because it uses an ion exchange resin, it is not suitable for industrial large-scale production due to the equipment required. Examples include being . In the present invention, as a result of repeated research on methods to eliminate these disadvantages, especially quality deterioration due to inorganic contamination due to neutralization, we have developed a reaction solution in which dibasic acidic amino acids are esterified in alcohol in the presence of hydrochloric acid. When epoxide compounds such as propylene oxide, butylene oxide or epichlorohydrin are added to the esterification reaction, the hydrochloric acid added for the esterification reaction easily reacts with these epoxide compounds.

It was found that the compound can be dissolved in alcoholic solution as a ruhydrin compound. Furthermore, according to this method, the free amino acid monoester precipitated as crystals in the system is surprisingly a high-quality amino acid monoester that does not require any means of purification, simply by isolating it through a furnace operation. And since it can be obtained in extremely high yields, it is difficult to use in large-scale industrial production.
It is extremely advantageous and its economical efficiency is also very good. In addition, the chlorohydrin compound produced by the reaction between the epoxide compound and hydrochloric acid is easily converted into an epoxide compound by the Alka River and can be reused. In other words, when alkali metal or alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide are applied to the reactor liquid from which the target product has been removed, the chlorohydrin compound easily turns into an epoxide compound. Since it is regenerated with a high yield, the epoxide compound, which is a gas at room temperature, can be gasified and introduced into the ester reaction solution for reuse.
Furthermore, the liquid epoxide compound can be isolated by distillation and reused as is. Dibasic acidic amino acids that can be used in this method are aspartic acid and glutamic acid, and when they are optically active (D-form or L-form)
It also includes the case where it is inactive (DL form). Alcohols used in the production of amino acid monoesters include:
For example, methanol, ethanol, n-prononanol,
It reacts with aliphatic alcohols such as isopro/gnol, n-butanol, isobutanol, t-butanol, cyclohexyl alcohol, aromatic aliphatic alcohols such as benzyl alcohol, and dibasic acidic amino acids such as phenol to form its monoester. Anything that forms can be mentioned. Epoxide compounds used as processing agents include ethylene oxide, propylene oxide, butylene oxide, epichlorohydrin, and the like. In carrying out the method of the present invention, the treatment with an epoxide compound can be carried out by introducing the epoxide compound dropwise or by gasification into the ester reaction solution.
The addition temperature of the epoxide compound differs depending on the epoxide compound used, but it is preferably in the range of 15 to 30 qo, and adding at a temperature of 30 qo or higher may cause the creation of gestel due to the action of hydrochloric acid and high temperature. This is not preferable because it also causes a decrease in the yield of amino acid monoester. The rate of reaction also depends on the epoxide used and the reaction temperature. For example, when propylene oxide is used, when 20q0 of propylene oxide is added dropwise to the ester reaction solution, crystallization of the amino acid monoester begins immediately and the reaction is rapid. Even when epichlorohydrin is used, when it is added dropwise to the ester reaction solution at 20°C, the amino acid monoester crystallizes out immediately. However, the reaction is slightly slower than when propylene oxide is used, but 20
When the reaction is allowed to take place in the afternoon for about 5 hours, the reaction is almost complete. In order to complete the reaction, the temperature can be further increased and the treatment can be carried out at elevated temperatures. For example, when methanol is used as the alcohol, the reaction is completed in one hour by heating the methanol to reflux. The hydrochloric acid used in the esterification reaction becomes a chlorohydrin compound and dissolves in alcohol, and this chlorohydrin can be completely removed by washing the crystallized amino acid monoester in a furnace and then washing it with alcohol. In this way, high-quality amino acid monoesters containing no inorganic salts can be obtained in high yield and through simple operations. Further, the embodiment will be explained by showing a specific example. However, these illustrations are for clarifying the gist of the present invention, and are not intended to limit the present invention. Example 1 350 methanol and 20.52 m of hydrochloric acid gas (0.5
62 mol).

To this hydrochloric acid-methanol solution, 75.1 units (0.511 mol) of L-glutamic acid is added at 20 qo. After lighting for 5 hours at the same temperature, epichlorohydrin 62.4 hours (
0.674 mol) was added dropwise in an amount of 20 to 25 qo. After heating at room temperature overnight, the precipitated crystals of free L-glutamic acid y-methyl ester were collected in a furnace and washed with methanol. Yield 70.2 days (yield 85.1%) Melting point 184~
186.500 Thin layer chromatography gives one spot (n-BuOH:AcOH: ratio ○ = 3:1:1)
Example 2 Hydrochloric acid gas 22.03 m (0.6 m) was added to 350 methanol
04 mol).

To this hydrochloric acid-methanol solution, 73.5 moles (0.5 mol) of L-glutamic acid was added at 20°C, and the mixture was heated at the same temperature for 5 hours. To the reaction solution, 42.1 hours (0.
725 mol) was added dropwise at 2.0°C. Immediately after the dropwise addition, free L-glutamic acid y-methyl ester precipitates out. After incubating overnight at room temperature, the crystals are taken out and washed with methanol. Yield: 69.72 min (yield: 86.6%), melting point: 185-186° C. Thin layer chromatography gives one spot. Example 3 21.9 mm (0.6 mol) of hydrochloric acid gas is blown onto 350 mm of methanol.

To this hydrochloric acid-methanol solution, 20 qo of L-aspartic acid (66.7 mol) is added. After incubating at the same temperature for 5 hours, Epicrohydrin 6 was added to the reaction solution.
6.5# (0.72 mol) is added dropwise. After heating the mixture at 20°C for 5 hours, the temperature was further raised and the mixture was heated under reflux for 1 hour.

After cooling, the precipitated free L-aspartic acid 3-methyl ester is taken out of the furnace and washed with methanol. Yield 64
．． 9 (yield: 88.0%), melting point: 181-1820, giving one spot on thin layer chromatography. Example 4 22.0 molar (0.6 mol) of hydrochloric acid gas was blown into 350 molar of ethanol.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ) is an epoxide compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R and n have the same meanings as above) of dibasic acidic amino acid ω-monoester, Production method.