MXPA00005683A - Sweetener compositions containing aspartame and aspartame derivative - Google Patents

Abstract

Excellent sweetener compositions containing aspartame (APM) and APM derivative and being similar to sucrose in tasting properties, which can be easily, uniformly and efficiently produced at a high purity by the process for producing N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine methyl ester by the reductive alkylation of APM and 3,3-dimethylbutyraldehyde, which comprises using 3,3-dimethylbutyraldehyde in an amount at most equimolar to APM for producing N-[N-(3, 3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine methyl ester from a portion of the APM existing in the reaction system, then separating the reducing agent from the liquid reaction mixture, and effecting crystallization followed by the separation of the crystals thus precipitated.

Description

SEEDLINESS COMPOSITIONS CONTAINING ASPARTAME AND ASPARTAME DERIVATIVE DESCRIPTION OF THE INVENTION The present invention relates to a process for the production of a sweetening composition containing the sweetening substances of aspartame (APM) and methyl ester of N- [N- (3, 3 -dimethylbutyl) -L-aspartyl] -L-phenylalanine, which can be abbreviated later to "N- (3, 3-dimethylbutyl) -APM", and simply referred to as "APM derivative", and the sweetening composition. In recent years, as eating habits have been improved to a high level, obesity has been the cause of excessive sugar intake and diseases accompanied by obesity. Therefore, the development of a low-calorie sweetening agent (sweetener) that replaces sugar has been in demand. Aspartame (APM), which is an excellent sweetener in safety and quality, is widely used as a sweetening agent. However, this is a bit problematic in stability. Under these circumstances, in the French Patent No. 2697844, it is established that derivatives are studied in which an alkyl group is introduced into an amino group of aspartic acid constituting the APM in an approach to slightly improve the stability and to improve the sweetening power, and among them the N - (3, 3-dimethylbutyl) -APM is remarkably improved in the sweetening potency. For the production of N- (3, 3-dimethylbutyl) -APM, a process for the reductive alkylation of APM under the coexistence of 3,3-dimethylbutylaldehyde with sodium cyanoborohydride in methanol (with reference to the specification FR 2697844) is known. , and a process for the reductive alkylation of APM 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 (with reference to WO95 / 30689). And yet, when a reaction is carried out according to the process described in the specifications of the above patent, 3, 3-dimethylbutylaldehyde and the APM do not react, or the methyl ester of N- [N, N-di (3 , 3-dimethylbutyl) -L-aspartyl] -L-phenylalanine, where 2 alkyl groups have been introduced thereto, are mixed in the reaction solution (mixture) or the crystals without purifying the product thereof, not to mention extension . The sweetening potencies of N- (3, 3-dimethylbutyl) -APM being a sweetener that has sweetness in a high degree and of the APM being an amino acid based sweetener, are reported to be respectively 10,000 times in relation to the weight (with reference to Japanese Patent Kohyou Publication JP-A-8-503206) and about 200 times the weight ratio (with reference to Japanese Patent Kokoku Publication JP-B-47-31031) of sucrose, respectively. The properties as sweetness for N- (3, 3-dimethylbutyl) -APM are not reported in detail, and yet the compound is extremely weak in anticipatory taste (which means that when a sweetener is put in the mouth it tastes sweet as early as sucrose), and extremely strong in subsequent flavor (which means that a sweetener subsequently tastes sweet to sucrose), in accordance with the present inventors' discoveries. It is strong in astringency (astringent taste) and badly balanced in its sweetness quality compared to sucrose. On the other hand, with respect to APM, its sweetness quality properties are weak in anticipated flavor, and strong in subsequent flavor, although they are not as bad as those in N- (3, 3-d? Met? Lbut? L) -APM. Consequently, either of both compounds has the properties of quality and sweetness which is weak in anticipated flavor and strong in subsequent flavor, and thus is out of sweetness quality, taking into account the standard that sucrose is naturally sweet. . With regard to the improvement in the properties of the sweetness quality, there are several proportions for improvement mainly in the subsequent taste (for example, with reference to Japanese Patent Kokai Publication JP-A-56-148255, JP-A-58-141760, JP-A-58-220668, etc. ). Methods for obtaining a natural quality of sweetness close to that of sucrose, for example, by the combination with sucrose (with reference to Japanese Patent Publication JP-A-57-152862), etc. they are among the propositions. On the other hand, it is possible that the anticipated flavor intensifies, the subsequent taste weakens, and also that the astringent taste weakens to balance The quality of the sweetness combining homogeneously and appropriately N- (3,3-dimethylbutyl) -APM being a sweetener having sweetness to a high degree with APM being an amino acid-based sweetener, in accordance with the discoveries found by the inventors in the present invention. Especially, by the homogeneous and appropriate combination of N- (3,3-dimethylbutyl) -APM which is weak in flavor anticipated with APM, it is improved in anticipated taste and with that it is expected to provide a sweetener that has sweetness to a high degree and a totally good quality of sweetness in balance, close to sucrose, compared to N- (3,3-dimethylbutyl) -APM or APM each alone. The sweetening potency of N- (3, 3-d? Met? Lbut? L) -APM is 10,000 times as much as that of sucrose in relation to weight, (with reference to the Japanese Patent Kohyou Publication JP-A-8- 503206) and consequently it is problematic to adjust a degree of sweetness while using it. Therefore, a combination of N- (3, 3-d? Met? Lbut? L) -APM with APM is required, which is appropriate for sweeteners, since not only does it improve the sweetness quality but also in the the uses of it. In view of the sweetness quality properties present in APM and in the APM derivative (N- (3,3-dimethylbutyl) -APM) described in the previous section, a problem to be solved by the present invention is to provide a process to conventionally and 'homogenously (uniformly) produce a sweetening composition containing the APM and N- (3, 3-d? met? lbut? l) -APM at a high yield and at a high purity which is improved as a sweetness, compared to the process for mixing APM crystals with crystals of APM derivative, after each one is produced separately, and also provides an excellent sweetening composition thus obtained. To solve the problem in the present invention, the present inventors have seriously studied and found the fact that in the process to produce N- [N- (3, 3-d? Met? Lbut? L) -L- - methyl ester. aspartyl] -L-phenylalanine by the reaction of APM with 3,3-dimethylbutylaldehyde for the alkylation, using 3, 3-d? meth? lbut? laldehyde in an amount at most equimolar, preferably about 0.0003-0.28 mol, more preferably about 0.0005-0.25 mol to 1 mol of the APM in the reaction to produce the APM derivative (N- (3,3-dimethylbutyl) -APM) from a portion of the APM existing in the reaction system, and then separating the reducing agent from the liquid reaction mixture, and carrying out the crystallization followed by the separation of the crystals thus precipitated, an excellent sweetening composition containing aspartame (APM) and N- [N- (3,3-dimethylbutyl) methyl ester) -The-aspartyl] -L-phenylalanine and having a preferred balance It can be easily, uniformly and efficiently produced at a high yield and a high purity, without producing N- [N, N-di (3, 3-d? met? lbut? l) methyl ester - La-aspartyl] -L-phenylalanine as a by-product, in which two alkyl groups are introduced, compared with those in the process to produce APM crystals and crystals derived from APM each separately, and thereafter mix the two types of crystals thus obtained separately and with this completes the present invention. That is, the present invention is directed to a process for the production of N- [N- (3-methyl ester, 3-dimethylbutyl) -L- -aspartyl] -L-femlalanma comprising an APM reaction with 3, 3-d? Meth? Lbut? Lalchidohide for reductive alkylation, the process for the production of a sweetening composition containing APM and the APM derivative, wherein the APM derivative is produced from a portion of APM using 3, 3-d? met? lbut? laldehyde in an amount at most equimolar to the APM in the reaction, the reducing agent being separates from the reaction solution, and the solution is subjected to crystallization followed by separation of the crystals thus precipitated. According to the production process thereof, a sweetening composition that homogeneously contains APM and APM derivatives can be produced. In the present invention, the following contents are additionally contained: 1. A sweetening composition containing APM and the APM derivative obtained in the aforementioned process for the production thereof in the present invention can be a preferable sweetener. 2. The composition as it was produced and mentioned above in the present invention, and which is in the dry form, may be preferable in particular for a sweetener. 3. The aforementioned sweetener composition obtained in the present invention, containing a sweetener carrier, if required, can be used for a sweetener or a sweetening agent. The sweetness can be provided to a material that demands a sweetness by using the composition for a material that demands a sweetness for animals such as humans, for example, food, cosmetics in the mouth (mouthwash, mouthwash, etc.), oral pharmaceuticals , etc. In the production or selection of the carrier, if employed, a suitable carrier can be produced or selected through the known methods for the production or selection of carriers thereof. . the aforementioned sweetening composition, wherein the APM and the APM derivative are contained in a ratio of APM to APM derivative being from 100 to about 0.05-50 by weight, may be preferable, particularly for use in a sweetener. 5. When the aforementioned sweetener composition can be produced according to the aforementioned process for the production thereof, wherein 3,3-dimethylbutylaldehyde is used in an amount of about 0.0003-0.28 mol, more preferably about 0.0005-0.25. by 1 mole of APM in the reaction for the reductive alkylation, a particularly desirable sweetening composition can be obtained. When an APM N- (3,3-dimethylbutyl) -APM derivative is produced in an APM reaction with 3,3-dimethylbutylaldehyde for reductive alkylation, using 3, 3-dimethylbutylaldehyde in an amount at most equimolar to APM, pref. In an amount of about 0.0003-0.28 mol, more preferably about 0.0005-0.25 mol per 1 mol of APM in the reaction, a portion of the present APM can be converted into the efficient APM derivative without producing the N- [N, N-di (3, 3-d? Met? Lbut? L) -La-aspartyl] -L-phenylalanine as a by-product. After the reaction is complete, when the used catalyst is separated, a solution containing APM and the APM derivative is obtained. By concentrating, if required, and subjecting the solution to crystallization followed by the separation of the thus precipitated crystals, a sweetening composition containing APM and the APM derivative particularly containing homogeneously (uniformly) APM and the APM derivative, preferably for a sweetener, can be produced . For the catalysts used in the reaction, platinum carbon, palladium carbon, platinum black, palladium black, etc. are known. (with reference to specification WO95 / 0689) are known, and yet, the species of the catalysts are not limited thereto. The catalysts that will be developed and provided in the future can also be used. For the solvent used in the reaction for the alkylation, a type of solvent selected from water, ethyl acetate, methyl acetate, acetic acid, toluene, hexane, tetrahydrofuran, acetonitrile, dimethoxyethane, ethyl ether, isopropyl alcohol, ethyl alcohol, methyl alcohol, dichloromethane, chloroform and 1,2-d • Chloroethane, or a mixed solvent obtained from 2 or more types of solvents selected from these previous solvents. It is necessary to make the concentration of APM in the reaction solution for a higher crystallization, to achieve a higher yield therefore. Therefore, it is desired to employ an alcohol-based solvent, or a mixed solvent obtained from the solvent and the other solvents for the solvent used in the reaction. However, in the event that there is a serious element or doubt as in the solvent remaining in the final product in view of the quality of the product, water or the mixed solvent of water and alcohol based on the solvents can be preferably used. For the subsequent treatment of the reaction solution, first, the catalyst used in the reaction of the solution is separated. For the reaction solution thus obtained, when it is obtained by the reaction using an alcohol-based solvent or mixed solvents of this solvent with the other solvent, the solvent is replaced by water as much as possible to minimize the solvent, which exists in the final product. This replacement is achieved by adding an adequate amount of water to the reaction solution, and then concentrating it. In the production of the sweetener composition, to control or regulate a weight ratio of the APM derivative by total amount of APM and the APM derivative contained in the final product of the composition, is achieved by adjusting an amount of 3, 3-d ? met? lbut? ladede? do, a reaction temperature and a reaction time, or adding before the start of the APM reaction in a fairly adequate amount in excess of the limit of its solubility, and dissolving the undissolved APM by heating or similar before separation of the catalyst, or also by adding an appropriate amount of APM to the solution after separation of the catalyst and dissolving the added APM. And, in the present invention, not only an operation step for dissolving the APM in the solvent used in the reaction and then starting the reaction, but also an operation for starting the reaction using as the starting material an APM solution or a solution that dissolves the APM as it is, obtained in a course for the production of APM. The reaction solution thus obtained can be subjected to a crystallization operation, such as a crystallization by cooling, crystallization by concentration, crystallization by neutralization, etc., after concentration as circumstances demand, crystallize the mixture containing the APM and the APM derivative. In case there is a lot of APM therein, since it is known that refined (minute) crystals can be formed or agitated, the solution can be subjected to crystallization either permanently (static crystallization) or to crystallization under stirring, if required , after crystallization or permanence, as described for example, in Japanese Patent Kokoku Publication JP-B-03-025438. For a good point (advantage) in the case of the production of the sweetener composition by the process, of course, the fact that a homogeneous mixture form is achieved as mentioned above, can be given in comparison to that obtained by the process to mix the APM crystals with the APM derivative crystals, each one produced separately. As regards the sorbet or the solution obtained in the crystallization, the final product can be obtained by subjecting the same to the separation of a solid material from a liquid, drying the solid material, and further granulating (pelletizing) if required. For the method of separating a solid material from a liquid, filtration and centrifugation are exemplified, and for the method for drying methods thereof with a vacuum dryer, a fluidized bed drier, a spray drier, a micrometric drier and the like are exemplified, and for the method granulation thereof, granulation = echo, wet granulation and the like are exemplified, and yet there is no limitation to these exemplified methods. There is no difficulty, when the sweetener composition obtained in the present invention can be used for a sweetener or a production thereof. For example, it can be easily conducted by applying known methods for the production of sweeteners or for use thereof in such case. The present invention is further illustrated specifically referring to the following examples. [EXAMPLE 1] APM (aspartame; 55.0 g, 0.180 mol) in the water content of 3.9% by weight and 3, 3-dimethylbutylaldehyde (2 ml, 0.016 mol) were added to water (1000 ml) and the resulting solution was maintained at 23 ° C. 5% palladium carbon (5.0 g) was added, and the solution was subjected to reductive reaction for 2 hours under a flow of hydrogen (H2) at a flow rate of 1000 ml per 1 hour. After that, the hydrogen flow was stopped, and the solution was heated to 69 ° C to completely dissolve the undissolved crystals. The catalyst was removed by filtration with a filter paper of 0.5 micrometer (μm), the resulting filtrate was allowed to remain in static crystallization at 5 ° C for 4 hours. The pseudosolid phase (sorbet) thus obtained was kept at 5 ° C under stirring overnight to prepare a solution.

The solution thus obtained was filtered through a 5 μm filter paper to separate a solid phase from a liquid phase. The solid phase was washed with 250 ml of water. The solid phase thus washed was dried under reduced pressure at 50 ° C overnight to obtain 43.6 g of the dried crystals in the water content of 2.7% by weight (APM: 95.8% by weight; N- (3, 3- dimethylbutyl) -APM: 2.5% by weight in the determination of high performance liquid chromatography.In the analysis of it by thin-layer chromatography (TLC), the methyl ester of N- [N, N-di (3, 3- dimethylbutyl) -L-aspartyl] -L-phenylalanine which is a dialkylated product was not contained therein.The composition thus obtained was homogenized (uniform) and improved as a sweetness giving an extremely excellent taste as a sweetener. the reaction for the reductive alkylation in the present invention, a production of the byproduct identified above is reduced or limited by using the APM in an amount at least equimolar to that of the 3, 3-dimethylbutylaldehyde Further, according to the process in the present invention, the composition sweetener containing the APM and the APM derivative improved in its flavor properties can be easy, uniform and also efficiently produced at high yield and high purity compared to the process for producing APM crystals and APM derivative crystals, each one separately, and then mixing the two types of crystals thus obtained separately.

Claims (6)

1. CLAIMS 1. A process for the production of N- [N- (3, 3-dimethylbutyl) -L-aspartyl] -L-phenylalanine methyl ester, characterized in that it comprises an APM reaction with 3,3-dimethylbutylaldehyde for reductive alkylation, the process for the production of the sweetening composition containing APM and the APM derivative, wherein the APM derivative is produced from a portion of APM using 3,3- 'dimethylbutylaldehyde in an amount at most equimolar to that of APM in the reaction, the reducing agent is separated from the reaction solution, and the solution is subjected to crystallization followed by separation of the crystals thus precipitated.
2. 2. The sweetening composition characterized in that it contains the APM and the APM derivative obtained in the process according to claim 1.
3. 3. The composition according to claim 2, characterized in that it is a dry sweetener composition.
4. 4. The sweetener is characterized in that it comprises the composition according to claim 3 and a carrier for the sweeteners.
5. The composition according to claim 2, characterized in that the APM and the APM derivative are contained in a ratio of APM to the APM derivative being from 100 to 0.05-50 by weight.
6. 6. The process according to claim 1, characterized in that 3, 3-dimethylbutylaldehyde is used in an amount of 0.0003-0.28 mol, per 1 mol of APM in the reductive alkylation reaction.