Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-06-09
2003-09-02
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S041000
Reexamination Certificate
active
06613933
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for separating and purifying two sweetening substances of aspartame (APM) and N-[N-(3,3-dimethylbutyl)-L-(&agr;-aspartyl]-L-phenylalanine methyl ester, which hereinafter may be referred to as “N-(3,3-dimethylbutyl)-APM” or “APM derivative”, by separating the two substances from each other.
2. Description of the Background
In recent years, eating habits have improved as awareness of obesity caused by excessive sugar intake and diseases accompanied by fatness has increased. Accordingly, the development of a low-calory sweetening agent (sweetener) that replaces sugar has been in demand. As a sweetening agent that is widely used at present, there is aspartame (APM) which is excellent in safety and quality of sweetness. However, the stability thereof remains problematic.
Under these circumstances, French Patent No. 2697844 describes the evaluation of derivatives in which an alkyl group is introduced on an amino group of aspartic acid constituting the APM in one approach to improve slightly the stability and to improve the sweetening potency. N-(3,3-dimethylbutyl)-APM is noted as markedly improving in the sweetening potency. For the production of N-(3,3-dimethylbutyl)-APM, a process for alkylating APM reductively under the coexistence of 3,3-dimethylbutylaldehyde with sodium cyanoborohydride in methanol (refer to the abovementioned FR 2697844 specification), and a process for alkylating APM reductively under the coexistence of 3,3-dimethylbutylaldehyde with platinum carbon as the catalyst in a mixed solvent of water and methanol at a pH value in a range of 4.5 to 5 (WO95/30689) are known. However, when a reaction is carried out according to the processes described in these patent specifications, 3,3-dimethylbutylaldehyde and APM are either both unreacted, or N,N-di(3,3-dimethylbutyl)-APM, produced as a by-product, wherein two alkyl groups have been introduced thereto, are mixed in the reaction solution (mixture) or the crude crystals of the product, to no small extent.
Among the compounds described, 3,3-dimethylbutylaldehyde is removed by drying under reduced pressure or washup with comparative ease, because it has a low boiling point or is soluble in a poor solvent for the N-(3,3-dimethylbutyl)-APM, such as hexane. On the other hand, it is difficult to remove APM and N,N-di(3,3-dimethylbutyl)-APM by crystallization from the residue from which the catalyst and the like have been removed as described in the above-mentioned patent specifications. Hence, the yield thereof is much reduced in order to obtain N-(3,3-dimethylbutyl)-APM having a satisfactory purity. In addition, the N,N-di(3,3-dimethylbutyl)-APM can not be recovered and used for the starting material, or etc., and therefore it is desired to suppress its production to the utmost. Since 3,3-dimethylbutylaldehyde is also problematic in odor (smell), it is desired to consume out the aldehyde as much as possible during the reaction. As one method of solving such an exhaust problem, a process for reacting APM with 3,3-dimethylbutylaldehyde in an excess of APM to the quantity of the aldehyde used might be considered. In such a case, where APM (unreacted) remains in the reaction solution (mixture), it would be desirable to establish a process for easily and efficiently separating APM from N-(3,3-dimethylbutyl)-APM, and thus separating and purifying each at a high purity. Unfortunately, such a process remains elusive.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a process for easily and efficiently separating the aspartame (APM) from N-(3,3-dimethylbutyl)-APM, and thus separating and purifying the two compounds each at a high purity, from an aqueous solution containing the APM and the N-(3,3-dimethylbutyl)-APM.
The above object and others are provided by a process for separating and purifying APM and N-[N-(3,3-dimethyl)-L-&agr;-aspartyl]-L-phenylalanine methyl ester, which entails subjecting an aqueous solution containing the APM and the N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine methyl ester to column chromatography using a non-polar, porous polymer-based resin to separate the APM from the N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In order to solve the problem and achieve the object in the present invention, the present inventors have surprisingly discovered that APM can be easily and efficiently separated from N-(3,3-dimethylbutyl)-APM, and thus these two compounds can be each separated and purified at a high purity, from an aqueous solution containing the APM and the APM derivative, or the like by passing such aqueous solution or the like through column chromatography with the use of nonpolar highly porous polymer resin utilizing differences in affinity between them to nonpolar highly porous polymer resin used in the chromatography. Based on the above findings, the present invention has been completed. Thus, the present invention provides to a process for separating and purifying APM and N-[N-(3,3-dimethylbutyl)-L-(&agr;-aspartyl]-L-phenylalanine methyl ester (APM derivative), which entails: subjecting an aqueous solution containing said APM and said APM derivative, or the like to column chromatography with the use of a nonpolar highly porous polymer based resin to separate the APM from the APM derivative.
In the column chromatography operation, for example, an aqueous solution containing above-mentioned two types of compounds may be passed through the column filled with the above-mentioned resin effect separation of each other for purification of each compound, using known methodologies utilizing the differences between the above-mentioned two compounds in affinity to the resin, and specifically the property that APM is weak in affinity to the resin as compared to the APM derivative.
Now, a process of column chromatography, wherein the above-mentioned resin may be used in the form of mixture with another carrier or in combination with another carrier, is used by the present invention, however, the operation for the column chromatography must the above-mentioned resin filled in the column to effectively separate APM from the APM derivative in the mixture thereof.
In the present invention, the following aspects are also entailed:
1. The above process, wherein said nonpolar highly porous polymer based resin contains an aromatic polymer based resin or is an aromatic polymer based resin.
In this case, the above-mentioned aromatic polymer based resin used as the nonpolar highly porous polymer based resin may be employed for all the nonpolar highly porous polymer based resin contained in the column or for a part thereof, and these methods of using the resin are all involved in the present invention.
2. The above process, wherein said aromatic polymer based resin contains at least one resin selected from the group consisting of DIAION SP resin and DIAION HP resin.
3. The above process, wherein said DIAION SP resin contains at least one resin selected from the group consisting of DIAION SP 850 and DIAION SP 207.
4. The above process, wherein said DIAION HP resin contains DIAION HP 20 resin.
As used herein, “DIAION” used for the carrier filled in the column is a trade name of Mitsubishi Chemical Corporation, and a carrier which may be essentially the same resin to any such DIAION in chemical constitution or composition and may have the same action to that of any such DIAION may be contained in the carrier having the above-mentioned trade name, even though it may not have such above trade name for the carrier.
5. In a process for production of N-(3,3-dimethylbutyl)-APM from APM as a starting material, the process for production of said APM derivative, i.e., N-(3,3-dimethylbutyl)-APM, wherein the APM or the fraction including APM separated and purified in any above process is used for said starting material of APM or a part thereof.
In this case, the process for the pr
Kishishita Akihiro
Nagashima Kazutaka
Ajinomoto Co. Inc.
Barts Samuel
Zucker Paul A.
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