Mitsui Toatsu Chemicals, Incorporated

Mitsui Chemicals, Inc.

Toshio Katoh

Akihiro Yamaguchi

Chojiro Higuchi

Ryuichi Mita

Takeshi Oura

Masanobu Ajioka

Hiroaki Tamatani

Yoshihiro Irizato

Makoto Sukegawa

Akinori Nagatomo

Masaru Wada

Masaharu Ohoka

Nobuyuki Kawashima

Takao Takano

Shousuke Nagai

Shinji Ogawa

Nobuhiro Kawashima

Susumu Fukawa

Katsuhiko Machida

A production process of high molecular weight polysuccinimide having a weight average molecular weight of 40,000 or higher is disclosed, which comprises the following steps: 1) mixing and heating aspartic acid and an acidic catalyst to produce a liquid, low molecular weight polymer mixture, 2) separating the acidic catalyst to appropriate extent from the liquid, low molecular weight polymer mixture, thereby directly changing a polymer-containing phase from a liquid phase into a solid phase to produce a solid, low molecular weight polymer mixture, and 3) conducting solid-state polymerization on the thus-obtained solid, low molecular weight polymer mixture. This process can be practiced in a simple apparatus, and is free of problems such as formation of a highly viscous phase, excessive formation of foam, and formation of a reaction mixture into coherent mass.

Production process of polysuccinimide

A process is disclosed for producing with good productivity a cross-linked polyaspartic acid resin having biodegradability and high water absorbency. The process features inclusion of one of the following steps: (a) a polysuccinimide, which has been brought into a dispersed state by a dispersant, and a cross-linking agent are reacted to produce the cross-linked polyaspartic acid resin; (b) imide rings of a cross-linked polysuccinimide are subjected to a hydrolysis reaction while controlling a swelling degree of a resulting gel, whereby the cross-linked polyaspartic acid resin is produced; and (c) a gel of a cross-linked polysuccinimide, which has been obtained by reacting a cross-linking agent to a solution of a polysuccinimide in an organic solvent, is disintegrated to subject imide rings of the cross-linked polysuccinimide to a hydrolysis reaction, so that the cross-linked polyaspartic acid resin is produced. The process may also include one or both of the following steps as needed: (d) a gel of the cross-linked polyaspartic acid resin is washed with water and/or a water-miscible organic solvent; and (e) the polysuccinimide is produced using a basic amino acid as a cross-linking agent.

Production process of cross-linked polysuccinimide resin

Production process of cross-linked polyaspartic acid resin

A cross-linked polymer containing, in its molecule, recurring units represented by the following formula (1), and having biodegradability and high water-absorbency: ##STR1## wherein R.sub.1 is a pendant group having at least one functional group selected from the group consisting of acidic groups and salts thereof, a glycino group and salts thereof, cationic groups and betaine groups; X.sub.1 is NH, NR.sub.1 ', R.sub.1 ' being an alkyl, aralkyl or aryl group, O or S; and n.sub.1 is 1 or 2.

Cross-linked polymer

A polymer containing the following monomer unit (I) and/or (II): ##STR1## and a process for preparing the polymer which comprises, in ring opening reaction of the polysuccinimide, opening the ring of polysuccinimide by using an amino acid ester having an extremely high reactivity in place of an .alpha.-amino acid having an extremely low reactivity. The polymer is characterized by having no irritation to organisms (e.g., eyes and skin), and for example, the polymer is useful in the industrial fields of fields of medical supplies, health, beauty and sanitary aids, quasi-pharmaceuticals, and the like.

Polymer containing monomer units of chemically modified polyaspartic

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.

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Kawasaki, Japan

Toshio Katoh