Mitsui Toatsu Chemicals, Incorporated

Takeshi Oura

Akihiro Yamaguchi

Chojiro Higuchi

Toshio Katoh

Ryuichi Mita

Masanobu Ajioka

Disclosed is an improved process for the preparation of an N-protected .alpha.-L-aspartyl-L-phenylalanine methyl ester from an N-protected L-aspartic anhydride and L-phenylalanine methyl ester, the improvement which comprises employing the L-phenylalanine methyl ester in the form of a mineral acid salt thereof and conducting the reaction either (a) in an organic solvent and in the presence of a salt of an organic carboxylic acid, or (b) in an organic solvent comprising an organic carboxylic acid and in the presence of at least one member of the group consisting of an alkali metal or an alkaline earth metal inorganic base, an ammonium alkali metal or alkaline earth metal salt of an organic carboxylic acid and ammonium carbonate. The starting N-protected aspartic anhydride, e.g., N-benzyloxycarbonyl-L-aspartic anhydride, can be produced by the reaction of N-protected aspartic acid with phosgene. When the N-protecting group sibenzyloxycarbonyl and the solvent is acetic acid, the desired product can be isolated from the reaction mixture in crystalline form in high purity by adding water thereto.

Preparation of N-protected .alpha.-L-aspartyl-L-phenylalanine methyl

A method for separating .alpha.-L-aspartyl-L-phenylalanine methyl ester (.alpha.-APM) from a solution containing .alpha.-APM and impurities associated with the production thereof which comprises adding a mineral acid or an organic sulfonic acid to the solution in an organic carboxylic acid or in a solvent containing an organic carboxylic acid, and isolating the pure salt of .alpha.-APM which precipitates therefrom.

Separation method of .alpha.-l-aspartyl-l-phenylalanine methyl ester

A method for preparing .alpha.-L-aspartyl-L-phenylalanine methyl ester (.alpha.-APM), substantially free from acid ion contamination, is disclosed which comprises the steps of contacting a solution of a mineral acid salt or an organic sulfonic acid salt of .alpha.-APM in an aqueous solvent with an anion exchange resin in free base form, separating the resin from the thus-produced solution of .alpha.-APM; and isolating the .alpha.-APM therefrom, preferably with regeneration and recycling the resin.

Method for preparing .alpha.-L-aspartyl-L-phenylalanine methyl ester

A cyclical process for producing and isolating a mineral acid salt of an amino acid methyl ester in high purity and yield from the reaction solution produced by esterifying an amino acid with methanol in methanol in the presence of a mineral acid, by cooling the resulting reaction solution to precipitate crystals of the mineral acid salt; filtering the crystals;

Preparation and isolation of mineral acid salt of an amino acid methyl

.alpha.-L-Aspartyl-L-phenylalanine methyl ester having low hygroscopicity is prepared by bringing a cake of .alpha.-L-aspartyl-L-phenylalanine methyl ester, which cake has been obtained by solid-liquid separation through a desired preparation process of .alpha.-L-aspartyl-L-phenylalanine methyl ester, into contact with an organic solvent of uniform phase so as to treat the cake with the organic solvent, subjecting the resulting mixture of the cake and organic solvent to solid-liquid separation to obtain a cake, and then drying the last-mentioned cake at a temperature not higher than 60.degree. C. The organic solvent is dry or contains water in an amount up to 30 wt.%.

Preparation process of .alpha.-l-aspartyl-l-phenylalanine methyl ester

.alpha.-L-aspartyl-L-phenylalanine methyl ester or the hydrohalide thereof is prepared by esterifying .alpha.-L-aspartyl-L-phenylalanine or .alpha.-L-aspartyl-L-phenylalanine which has been formed in situ by treating an N-protected-.alpha.-L-aspartyl-L-phenylalanine in an aqueous solution of sulfuric acid or a methanol-containing aqueous solution of sulfuric acid in the presence of an alkali metal halide or alkaline earth metal halide in a medium composed of sulfuric acid, water and methanol, thereby to allow the resulting .alpha.-L-aspartyl-L-phenyl-alanine methyl ester to precipitate as its corresponding hydrohalide, and then isolating the hydrohalide; and when the preparation of the methyl ester is desired, neutralizing the hydrohalide.

Preparation process of .alpha.-l-aspartyl-l-phenyl-alanine methyl ester

A method for preparing .alpha.-L-aspartyl-L-phenylalanine methyl ester having improved solubilization by the isolation thereof from an aqueous medium containing at least one additive selected from the group consisting of sodium alginate, sodium salt of carboxymethylcellulose, sodium starch glycolate and sodium polyacrylate.

Isolation of alpha-l-aspartyl-l-phenylalanine methyl ester from aqueous

This invention relates to an improved process for preparing .alpha.-L-aspartyl-L-phenylalanine methyl ester. More specifically, it relates to a process for preparing .alpha.-L-aspartyl-L-phenylalanine methyl ester which comprises treating, as a raw material, N-formyl-.alpha.-L-aspartyl-L-phenylalanine in methanol in the presence of an acid to form .alpha.-L-aspartyl-L-phenylalanine dimethyl ester, hydrolyzing the .alpha.-L-aspartyl-L-phenylalanine dimethyl ester by bringing it into contact with hydrochloric acid in the presence of methanol as desired, separating the thereby-precipitated .alpha.-L-aspartyl-L-phenylalanine methyl ester hydrochloride and neutralizing the hydrochloride. Further, this invention also provides a process for preparing .alpha.-L-aspartyl-L-phenylalanine methyl ester capable of using, as a raw material, N-formyl-.alpha.-L-aspartyl-L-phenylalanine which contains N-formyl-.beta.-L-aspartyl-L-phenylalanine in an amount of 30% by weight or less.

Preparation process of .alpha.-L-aspartyl-L-phenylalanine methyl ester

Disclosed herein is a process for preparing .alpha.-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride from 5-benzyl-3,6-dioxo-2-piperazine acetic acid or its methyl ester, prepared without using L-penylalanine methyl ester which involves problems in its stability, as a raw material. Specifically, the process comprises: bringing 5-benzyl-3,6-dioxo-2-piperazine acetic acid in the presence of methanol or 5-benzyl-3,6-dioxo-2-piperazine acetic acid methyl ester in the presence or absence of methanol into contact with hydrochloric acid; isolating the thereby deposited .alpha.-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride with an alkali as required. Preparation processes of 5-benzyl-3,6-dioxo-2-piperazine acetic acid or its methyl ester are also disclosed.

The present invention relates to a process for preparing .alpha.-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride. .alpha.-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride is prepared by a process comprising: condensating N-formyl-L-aspartic acid anhydride and L-phenylalanine in water or in water containing methanol at a pH in the range of 7-12 to form N-formyl-.alpha.-L-aspartyl-L-phenylalanine; acidifying the reaction mixture successively with hydrochloric acid in the presence of methanol without isolating the N-formyl-.alpha.-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol for reaction and thereby to deposit .alpha.-L-aspartyl-L-phenylalanine methyl ester hydrochloride; separating the .alpha.-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride as required.

This invention relates to an improved process for preparing N-formyl-.alpha.- aspartyl phenylalanine. More specifically, it relates to a process for preparing N-formyl-.alpha.-aspartyl phenylalanine by condensating N-formyl aspartic acid anhydride and phenylalanine which comprises effecting the condensation reaction in a water medium while maintaining the pH during the reaction in the range of 7-12 and at a reaction temperature of 50.degree. C. or below.

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Zushi, Japan

Takeshi Oura