KR920008341B1 - Process for the preparation of l-phenyl alaline methylester - Google Patents

Abstract

A process for preparing L-phenylalanine methylester comprises (a) adding H2SO4 as a catalyst in excess amount of methanol and inserting L-phenylalanine, (b) reacting the mixture at 64.7-85 deg.C for 2 hrs under reflux, (c) neutralyzing the obtd. L- phemylalanine methylester sulfate with alkali soln., and (d) extracting it with an organic solvent selected from chloroform, toluene or ethylacetate. Pref. the molar ratio of methanol to L- phenylalamine is 10:1, and the using amount of H2SO4 to L- phenylalanine is 4 equivalene or more.

Description

Method for preparing L-phenylalanine methyl ester

The present invention relates to a method for producing L-phenylalanine methyl ester which is a raw material for L-aspartyl-L-phenylalanine methyl ester (aspartame).

(L-phenylalanine methyl ester)

The esterification reaction has been known since 1895 when the esterification method of Fisher & A. Speyer was published, and various kinds of organic and inorganic acids have been used as catalysts.

Lewis Acil, which has been generally used as a reaction catalyst, is a reversible reaction in which water is generated during the esterification reaction and acid-hydrolysis occurs simultaneously, which causes a decrease in yield (Advanced Organic Chemistry, Fleser & Fieser, ED. Maruzen, pp 372-373, 1961). In this way, by using acid chloride as a catalyst in order to prevent the production of water, which causes acid-hydrolysis, the cause of yield reduction can be eliminated (Korean Patent Application 88-17932).

However, acid-chloride is very harmful to the human body due to its high toxicity and has a problem of requiring a special facility for storage and reaction due to strong corrosiveness caused by the generated gas.

Because of the toxicity and corrosiveness of these acid-chloride catalysts, it is very important to use a catalyst which maintains a high yield and has few problems in the preparation of the target product.

An object of the present invention is to propose a method of selecting and preparing a catalyst that can produce a high yield of the target without the same problems as the acid-chloride catalyst in the production of L-phenylalanine metelester.

In particular, by using a catalyst more economical than acid-chloride to lower the production cost and to facilitate the production of the target.

The present inventors add an excess of sulfuric acid to the reaction solution of L-phenylalanine and metalol using dehydration of Lewis acid sulfuric acid among known catalysts, and then reflux the L-phenylalanine methyl ester using an acid catalyst. Compared with the production method, a higher yield was obtained, and the reaction could be carried out under mild conditions.

Esterification using sulfuric acid catalyst has already been published. In US Patent 3933781, L-aspartyl-L-phenylalanine methyl ester was prepared by reacting 0.16 mole of L-aspartyl-L-phenylalanine and 0.37N sulfuric acid-methanol solution (containing 0.2 m mole of sulfuric acid). In addition, it is known to use hydrochloric acid, sulfuric acid, phosphoric acid, bromine, and the like as a catalyst in preparing salts of amino acid esters (US Patents 3808190, 3879372).

However, the esterification of amino acids using sulfuric acid catalysts, especially methyl esterification reactions, yielded lower yields than acid-chloride catalysts due to the fact that the proper amount of sample and the exact reaction conditions for the production of high yields were not established.

The inventors added sulfuric acid (4 equivalents to L-phenylalanine) to the excess methanol (molar ratio to L-phenylalanine 10/1) at room temperature over 1 hour, and then slowly added L-phenylalanine, followed by 64.7 ° -85 ° C. L-phenylalanine methyl ester sulfate having a yield of 96% was prepared by refluxing for 2 hours, and methanol was distilled according to a known method, a little water was added and neutralized with an alkaline solution, followed by chloroform, toluene, Extraction with ethyl acetate and the like yielded a yield of 95% L-phenylalanine methyl ester solution. In the present invention, the amount of methanol does not have a large effect on the reaction when the molar ratio of 10/1 or more to L-phenylalanine is present, but a molar ratio of 10 times to L-phenylalanine is suitable in terms of economics.

The present invention will be described in more detail with reference to Examples.

Example 1

320.4 g of methanol was added to a four-necked flask equipped with a reflux condenser and an electric stirrer. 196.16 g of sulfuric acid was added at room temperature over 1 hour, 1 mole of L-phenylalanine was slowly added thereto, and the mixture was heated to 64.7 ° -85 ° C. for reflux for 2 hours. . The reaction solution contained 6.6 g of unreacted L-phenylalanine as a result of HPLC analysis, indicating 96% conversion to L-phenylalanine methylester sulfate.

The reaction solution was neutralized with an alkaline solution according to a known method and extracted with chloroform, which is a non-aqueous organic solvent, to obtain a L-phenylalanine methyl ester solution having a total yield of 95%.

TABLE 1

Amount of unreacted L-phenylalanine over reflux time

Example 2

The results of the same procedure as in Example 1 with varying amounts of sulfuric acid are shown in Table 2.

TABLE 2

Amount of Unreacted L-Phenylalanine with Varying Sulfuric Acid

Example 3

320.4 g of methanol was added to a four-necked flask equipped with a reflux condenser and an electric stirrer, and 147.1 g of sulfuric acid was added at room temperature over 1 hour, and 1 mole of L-phenylalanine was slowly added thereto, and the result was analyzed by heating to 64.7 ° -85 ° C. over time. Is shown in Table 3.

TABLE 3

Amount of unreacted L-phenylalanine over reflux time

Example 4

The result obtained by changing the reflux temperature in Example 1 and reacting in the same process is shown in Table 4.

TABLE 4

The amount of unreacted L-phenylalanine at reflux temperature

Claims (2)

In the production of L-phenylalanine methyl ester, sulfuric acid is added to the excess methanol as a catalyst at room temperature, and L-phenylalanine is slowly added thereto, and then refluxed at 64.7 ° -85 ° C. for 2 hours, thereby producing L-phenylalanine methyl ester. A method of preparing sulfate and neutralizing it with an alkaline solution according to a known method and then extracting it with a non-aqueous organic solvent to obtain an L-phenylalanine methyl ester solution. The method of claim 1 wherein the amount of methanol is a molar ratio of 10: 1 to L-phenylalanine and the amount of sulfuric acid is used at least 4 equivalents to L-phenylalanine.