KR880002303B1 - Process for the preparation of d-l-aspartyl-l-phenylalkylester - Google Patents

Abstract

α-L-Aspartyl-L-phenylalanine alkylesters (I) (R1=C1-5 alchol) were prepd. Thus, fluorenyl-methoxycarbonyl-aspartic acid was reacted with dicyclohexyl carbodiimide in THF for overnight at room temp. to give the corresp. anhydride, which was acylated with N- phenylalane methylester in ethylacetate for 6 hr at room temp. with stirring to give N-fluorenyl-methoxycarbonyl-L-aspartyl- Lphenylalaninemethylester. This ester was hydrogenated on 5% Pd/c catalyst, filtered, and acid; fied with 14% ammonia water to produce (I)(R1=Me).

Description

Method for preparing α-L-aspartyl-L-phenylalanine alkyl ester

The present invention relates to a method for producing α-L-aspartyl-L-phenylalanine alkyl ester represented by the following structural formula.

In the above structural formula, R1 is a lower alcohol group having 1-5 carbon atoms such as methyl group, ethyl group, and isopropyl group.

Α-L-aspartyl-L-phenylalanine methyl ester, also known as aspartame, is a low-calorie source and is widely used in beverages, and in recent years, consumption is rapidly increasing as an alternative sweetener.

Conventional methods include the preparation of α-L-aspartyl-L-phenylalanine alkyl esters according to US Patent No. 3,786,039 and Japanese Patent Application Laid-Open No. 57-25538, and the like. These methods include L-aspartic acid and L-phenylalanine. As a method of preparing by combining peptite, aspartic acid is reacted with acetic anhydride in an organic solvent to form N-formyl-L-aspartic anhydride, carbobenzooxy-L-aspartic acid anhydride, and P-methoxy carbobenzooxy-L -Asparagine anhydride was prepared, and then methyl, ethyl, propyl ester of L-phenylalanine was combined with an organic solvent in a solvent, and then a protecting group was removed with a protecting catalyst to prepare a target in a yield of about 60%. The process of converting cargo or acid anhydride was difficult and complicated, causing problems in manufacturing. Scheme A

Scheme A

The present invention will be described in detail the specific manufacturing method as a method that can be easily carried out industrially to eliminate the drawbacks of the above method. In other words, aspartic acid of formula (II) is reacted with fluorenine-methoxychloride of formula (III) to prepare an acid anhydride of formula (IV).

In this case, as the non-acidic dehydrating agent, dicyclohexyl carbodiimide of the following structural formula (V) is used. Thus, an acid anhydride (IV) can be easily produced in good yield and reacted with L-phenylalanine alkyl ester of the following structural formula (VI). The target product of Structural Formula (I) was prepared. (Scheme B)

Here, fluorenyl-methoxy chloride refers to a fluorenyl-methoxy derivative as a known substance (Fluorenylmethyl chloro formate. Reagent for Organic Synthesis, Vol. 3, P. 145, 1792).

Where R1 is as described above.

Scheme B

In general, it is well known to prepare acid anhydrides or acid chlorides using acetic anhydride for acylation in the process of preparing α-L-aspartyl-L-phenylalanine alkyl esters. If water is not completely removed during the process, it is easily hydrolyzed to the acid by reacting with water, which has been a factor of lowering the yield of the target product.

In order to compensate for this drawback, in the present invention, the acid anhydride is produced quantitatively by using a catalyst (IV) which easily absorbs the water generated during the production of the acid anhydride and converts it to the diacclohexyl urea of the following structural formula (L). The desired compound of formula (I) was prepared in good yield by reaction with -phenylalanine alkyl ester.

In the present invention, as the solvent used in the production of acid anhydride, ethyl ether, methyl propionate, tetrahydrofuran, dioxane ether, chloroform, NN-dimethyl formamide, benzene, toluene, glacial acetic acid, etc. are used, and double glacial acetic acid is used. Was the best and the reaction temperature was obtained in the best yield at room temperature.

The solvent used for (IV) and (VI) peptide binding was best reacted in an aqueous ethyl acetate solution and an aqueous tetrahydrofuran solution, and the reaction temperature was reacted at room temperature to remove the solvent under reduced pressure, and an aqueous solution of ethane acetate was added to the catalyst. Hydrogenation is carried out using 5% -Paradium carbon for 3-10 hours, the catalyst is removed and congo red acidified with ammonia water to precipitate crystals. This crystal was recrystallized from water to obtain the target product in 70% yield.

Example 1

355 g of N-Fluorenyl-methoxycarbonyl-aspartic acid was dissolved in 2 L of tetrahydrofuran, 30 g of dicyclohexyl carbodiimide was added, and left to stand overnight, followed by filtration and N-Fluorenyl-methoxycarbonyl-aspartic acid. 340 g of anhydride was dissolved in an ethyl acetate solution, and 179 g of N-phenylalanine methyl ester was added and mixed, followed by stirring at room temperature for 6 hours.

After completion of the coupling reaction, 500 ml of 1N hydrochloric acid was added to remove the aqueous layer containing unreacted -L-phenylalanine methyl ester, and the pH was adjusted with 5N hydrochloric acid to adjust N-fluoroenyl-methoxycarbonyl-L-aspartyl-L-phenylalanine methyl. 415.2 g of ester were obtained.

The reaction was carried out using a 5% palladium-carbon catalyst for 6 hours at reduced pressure and normal temperature, followed by filtration of the catalyst and acidification with 14% aqueous ammonia and filtration of the resulting crystals to give 248.5 g of α-L-aspartyl-L. -Phenylalanine methyl ester was obtained. The yield was 70% from N-Fluorenyl-methoxycarbonyl-aspartic anhydride.

Example 2

After dissolving 340 g of N-fluoroenyl-ethoxycarbonyl-aspartic anhydride in tetrahydrofuran aqueous solution, 179 g of L-phenylalanine methyl ester was added to 2 L of vinegar acid, mixed and stirred at 40 ° C. for 3 hours, and then as in Example 1 It carried out and obtained 241.4 g of (alpha) -L- aspartyl- L-phenylalanine methyl esters.

The yield for the aspartic acid derivative was 71%.

Claims (1)

Aspartic acid of formula (II) and formula (III) convert fluorenyl-methoxychloride to known ethyl ether, methyl propionate, tetrahydrofuran, dioxane ethyl ether, coloform, NN-dimethylformamide, benz In an organic solvent such as toluene, glacial acetic acid, an acid anhydride of formula (IV) was prepared with dicyclohexyl carboimide, a nonacidic dehydrating agent of formula (V), and then reacted with L-phenylalanine methyl ester of formula (VI). Α-L-aspartyl-L-phenylalanine methyl ester of (I). [Formula II];

[Formula III]

N-Fluorenyl-methoxychloride [Structure Formula Ⅴ]

Dicyclohexylcarbodiimide [Formula IV]

N-Fluorenyl-methoxycarbonyl-aspartic anhydride [Structure Formula VI]

L-phenylalanine methyl ester [Formula I]

L-L-aspartyl-L-phenylalanine methyl ester