Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-03-13
2001-11-13
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S040000
Reexamination Certificate
active
06316657
ABSTRACT:
TECHNICAL FIELD OF INVENTION
The present invention relates to a novel process for purification or recovery of a sweetener having a high degree of sweetness, and more particularly, relates to a process for purification or recovery of N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester represented by the following general formula (1) described in the Kohyou Patent Publication, Tokuhyouhei-JP-A-8-503206(503206/1996) from PCT.
BACKGROUND OF ART
Since the compound in the present invention is synthesized by reacting &agr;-L-aspartyl-L-phenylalanine methyl ester with 3,3-dimethylbutyl aldehyde as described in the publication, for example, Tokuhyouhei-JP-A-8-503206, EP Patent Publication WO95/30689, or etc., it is difficult to avoid the mixing of unreacted &agr;-L-aspartyl-L-phenylalanine methyl ester into N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester. Accordingly, it is most important to remove &agr;-L-aspartyl-L-phenylalanine methyl ester for the purification of N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester. It is described in the publication of Tokuhyouhei-JP-A-503206 that the compound in the present invention can be purified by a standard technique such as recrystallization and chromatography. The chromatography is not an appropriate technique for an industrial purification method. And, the recrystallization is in most common use for an industrial purification method, and however since the desired compound is dissolved in the mother liquor, and the dissolved compound is lost away, it is difficult to say that it is an efficient technique in view of the yield. Accordingly, a recovering method from the mother liquor is employed industrially by necessity to improve the yield. In the meantime, there is little difference between the solubility of &agr;-L-aspartyl-L-phenylalanine methyl ester and the solubility of N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester at a temperature of from 5 to 25° C. in the water which is usually employed for the solvent in the recrystallization of peptides and thus an amount of N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester nearly equal to that of &agr;-L-aspartyl-L-phenylalanine methyl ester is lost in the mother liquor through the recrystallization step. In addition, a recovering method from the mother liquor is not described in any specifications of the above-mentioned 2 prior patent publications. Typically, the object (desired) compound may be recovered by concentrating and cooling the mother liquor to crystallization, and however this recovering method requests burdensome steps or operations on the concentration, crystallization and separation, and further is not efficient also from the recovery rate (yield) thereof, because the object compound is lost in the mother liquor.
OBJECT OF INVENTION
The problem to be solved by the present invention, that is the object of the present invention, is to provide an effective process for purification or recovery of N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester.
DISCLOSURE OF INVENTION
In order to solve the problem, the present inventors have studied earnestly a process to purify N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester represented by the above-mentioned general formula containing at least &agr;-L-aspartyl-L-phenylalanine methyl ester as an impurity, and also a process to recover the object compound from an aqueous solution of N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester containing at least &agr;-L-aspartyl-L-phenylalanine methyl ester as a dissolved substance, and consequently have found unexpectedly that high purity N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester not containing &agr;-L-aspartyl-L-phenylalanine methyl ester can be obtained by contacting N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester containing at least &agr;-L-aspartyl-L-phenylalanine methyl ester as an impurity, with the mixed solvents having two layers of one layer given from at least one organic solvent (one or more organic solvents) which does not mix (is immiscible) with water homogeneously and one layer of water to extract N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester in the side of the organic solvent layer in the separated layers, and on the other hand, to extract &agr;-L-aspartyl-L-phenylalanine methyl ester in the side of the water layer therein for selectivity. In addition, they have found that N-(3,3-dimethylbutyl) -&agr;-L-aspartyl-L-phenylalanine methyl ester can be recovered from N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester containing &agr;-L-aspartyl-L-phenylalanine methyl ester by contacting an aqueous solution of such impure N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester containing &agr;-L-aspartyl-L-phenylalanine methyl ester as a dissolved substance with at least one organic solvent which does not mix with water homogeneously to extract such desired compound in the side of the organic layer. The present invention has been completed based on the above findings.
Namely, the present invention is directed to a process for purification of N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester represented by the above mentioned general formula comprising the step of: contacting impure N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester containing at least &agr;-L-aspartyl-L-phenylalanine methyl ester as an impurity, with the mixed solvents having two layers of one layer given from at least one organic solvent (one or more solvents) which does not mix (is immiscible) with water homogeneously and one layer of water to extract N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester in the organic layer.
The present invention includes the following contents:
[1] The above purification process, wherein for the said at least one organic solvent (one or more solvents) which does not mix with water homogeneously, at least one organic solvent selected from the group consisting of toluene, ethyl acetate and butyl acetate is used.
[2] A process for recovery of N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester represented by the above mentioned general formula (1) comprising the step of: contacting an aqueous solution of N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester dissolving at least &agr;-L-aspartyl-L-phenylalanine methyl ester as an impurity, with at least one organic solvent (one or more solvents) which does not mix with water homogeneously to dissolve and extract N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester in the organic solvent layer.
[3] N-(3,3-dimethylbutyl)-&agr;-L-aspartyl-L-phenylalanine methyl ester as obtained in the above any processes for the purification or recovery thereof.
EMBODIMENTS OF INVENTION
For the examples of organic solvents which do not mix (are immiscible) with water homogeneously usable for the present invention, aromatic hydrocarbons such as toluene and xylene, fatty acid esters such as ethyl acetate and butyl acetate, and halogenated hydrocarbons such as methylene chloride and chloroform are cited. Among them, toluene, ethyl acetate and butyl acetate are preferably employed in view of an industrial application.
As the organic solvent, any organic solvents which do not mix with water homogeneously may be employed in the present invention, and a mixture of plural organic solvents which may form a separated layer against the water layer in the solution can also be employed. For the mixed solvents having 2 layers, typically the mixed solvents forming 2 layers wherein one layer is separated from the water layer in the solution is employed. The mixed solvents forming 3 layers separated therein may be also employed on circumstances.
For the quantity used of the organic solvent (one or more solvents), there are no special limitations thereon. The yield is improved higher as the rate of the quantity used of the
Ajinomoto Co. Inc.
Chaudhry Mahreen
Killos Paul J.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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