Process for purification of aspartame derivative

Details Process for purification of aspartame derivative Process for purification of aspartame derivative

2000-02-29

2002-01-01

Killos, Paul J. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S040000

Reexamination Certificate

active

06335461

ABSTRACT:

TECHNICAL FIELD OF INVENTION
The present invention relates to a process for purification of a sweetening substance of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine methyl ester represented by the following formula (1), which may be abbreviated to “N-(3,3-dimethylbutyl)-APM” or “APM derivative”, and to a process for production of high purity APM derivative.
BACKGROUND OF ART
In recent years, as eating habits have been improved to a high level, fatness caused by excessive sugar intake and diseases accompanied by fatness have been at issue. Accordingly, the development of a low-calory sweetening agent (sweetener) that replaces sugar has been in demand. As a sweetening agent that has been widely used at present, there is aspartame (APM, represented by the following formula (2)) which is excellent in safety and quality of sweetness. However, this is somewhat problematic in stability.
In the French Patent No.2697844 specification, it is stated that derivatives in which an alkyl group is introduced on an amino group of aspartic acid constituting the APM are studied and N-(3,3-dimethylbutyl)-APM represented by the above-mentioned formula (1) is markedly improved in the sweetening potency. For the production of N-(3,3-dimethylbutyl)-APM, a process for alkylating APM reductively in the presence of 3,3-dimethylbutylaldehyde with sodium cyano borohydride in methanol (refer to FR 2697844 specification), and a process for alkylating APM reductively in the presence of 3,3-dimethylbutylaldehyde with platinum carbon as the catalyst (refer to WO95/30689 specification) are known. And however, a reaction is carried out according to descriptions in such above patent specifications, 3,3-dimethylbutylaldehyde and APM both unreacted, or N,N-di(3,3-dimethylbutyl)-APM into which 2 alkyl groups have been introduced, represented by the following formula (3) are mixed in the reaction solution (mixture) and the crude crystals of the product, to no small extent.
Of the compounds stated above, 3,3-dimethylbutylaldehyde is removed by dryness under reduced pressure or washing (washup) with comparative ease, because it has a low boiling point or is soluble in a bad solvent such as hexane. On the other hand, it is difficult to remove APM and N,N-di(3,3-dimethylbutyl)-APM by recrystallizing once or twice the residue from which the catalysts has been removed as described in the above-mentioned patent specifications, and accordingly it is not possible to obtain N-(3,3-dimethylbutyl)-APM having satisfactory purity. Particularly, when APM is remained therein, it is difficult to remove it by crystallization. Because 3,3-dimethylbutylaldehyde is problematic in odor (smell), in the reaction it is desirable to consume out the aldehyde as much as possible by using excess of APM. In such case, the APM (unreacted) is remained in the reaction solution, and therefore it is important to establish a method for removal thereof efficiently.
PROBLEM TO BE SOLVED BY INVENTION
The problem to be solved by the invention is to provide, in the reductive alkylation of aspartame (APM) with 3,3-dimethylbutylaldehyde to produce N-(3,3-dimethylbutyl)-APM, a process for an effective separation or removal of APM remained in the reaction solution or the crude crystals of the product, or N,N-di(3,3-dimethylbutyl)-APM produced as the by-product therein.
DISCLOSURE OF INVENTION
In order to solve the problem, the present inventors have studied earnestly a process to purify N-(3,3-dimethylbutyl)-APM, and found the fact that N-(3,3-dimethylbutyl)-APM can be easily purified utilizing differences in solubility between APM and N-(3,3-dimethylbutyl)-APM in various solvents, differences in crystallinity between N-(3,3-dimethylbutyl)-APM and N,N-di(3,3-dimethylbutyl)-APM in various crystallizing solvents and differences in affinity to the carriers used on chromatography. Based on the above findings, the present invention has been completed.
That is to say, the present invention is directed to, in a process for separation and purification of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine methyl ester comprising the steps of alkylating reductively APM with 3,3-dimethylbutylaldehyde to produce the APM derivative represented by the above-mentioned formula (1), i.e., N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine methyl ester, and separating the APM derivative from the reaction solution for purification thereof, the improvement comprising the steps:
extracting said APM derivative with an organic solvent from said reaction solution concentrated or from crude crystals of the product obtained from said reaction solution; or washing said reaction solution concentrated or said crude crystals with an organic solvent, to dissolve said APM derivative therein, and thereby to separate and remove APM remained in said reaction solution at the time of completion of the reductive alkylation therefrom, and
separating an impurity contained in the organic solvent, i.e., N,N-di(3,3-dimethylbutyl)-APM represented by the above-mentioned formula (3) to be removed by using at least one operation selected from the following operations, A-D:
Operation A: Operation for crystallization of said APM derivative to separate (weeding out) and remove N,N-di(3,3-dimethylbutyl)-APM dissolved in the mother liquor therefrom;
Operation B: Operation for separating and removing N,N-di(3,3-dimethylbutyl)-APM on chromatography therefrom;
Operation C: Operation for separating and removing N,N-di(3,3-dimethylbutyl)-APM therefrom on extraction therefor; and
Operation D: Operation for separating and removing N,N-di(3,3-dimethylbutyl)-APM by adsorbing the same to the activated charcoal on treatment with activated charcoal.
In the present invention, the following contents are contained.
1. The above process, wherein the organic solvent used for solution of the APM derivative in the extraction of the desired product from the solution obtained by concentrating the reaction solution or the washup (washing) of the crude crystals of the product is one solvent or a mixed solvent of more than one solvents, selected from the group consisting of ethyl acetate, methyl acetate, toluene, hexane, tetrahydrofuran, acetonitrile, dimethoxyethane, ethyl ether, isopropyl alcohol, ethyl alcohol, methyl alcohol, dichloromethane (methylene chloride), chloroform, acetone and methyl ethyl ketone.
2. The above process, wherein the organic solvent used for crystallization of said APM derivative is one solvent or mixed solvent of more than one solvents, selected from the group consisting of ethyl acetate, methyl acetate, toluene, hexane, tetrahydrofuran, acetonitrile, dimethoxyethane, ethyl ether, isopropyl alcohol, ethyl alcohol, methyl alcohol, dichloromethane (methylene chloride), chloroform, acetone and methyl ethyl ketone, or a mixed solvent of water and at least one solvent selected from the group consisting of
tetrahydrofuran, acetonitrile, isopropyl alcohol, ethyl alcohol, methyl alcohol, acetone and methyl ethyl ketone.
3. The above process, wherein the chromatography is at least one of column chromatography having silica gel for a carrier, and column chromatography having activated charcoal for a carrier.
4. In a process for production of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine methyl ester or production of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine methyl ester and N,N-di(3,3-dimethylbutyl)-APM comprising the step of separating N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine methyl ester and N,N-di(3,3-dimethylbutyl)-APM each other from a mixture containing at least said two compounds, the improvement comprising the step of:
subjecting said mixture to at least one operation selected from the following operations: A-D:
Operation A: Operation for crystallization of said APM derivative to separate (weeding out) and remove N,N-di(3,3-dimethylbutyl)-APM dissolved in the mother liquor therefrom;
Operation B: Operation for separating and removing N,N-di(3,3-dimethylbutyl)-APM on chrom

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