MXPA96005244A - Improved procedure for the preparation of a compact derived from aspartame, which is useful as a edulcorative agent - Google Patents

Abstract

The present invention describes a method for the preparation of the N- (N- (3,3-dimethylbutyl) -L-alpha-aspartyl) -L-phenylalanine 1-methyl ester of the formula (I), useful as a sweetening agent , where the process is characterized in that a hydroalcoholic solution, with pH 4.5 to 5, of aspartame and 3,3-dimethylbutyraldehyde is treated, at room temperature, with hydrogen and at a pressure equal to or less than 1 bar, in the presence of a catalyst which is selected from the group comprised of platinum or palladium on activated carbon or in the form of black platinum or palladium black, and where the formed product is purified by means of precipitation and filtration, after the removal of the alcoholic part of the solvent by half of vac

Description

IMPROVED PROCEDURE FOR THE PREPARATION OF A COMPOUND DERIVED FROM ASPARTAME, WHICH IS USEFUL AS A SWEETENING AGENT. DESCRIPTION OF THE INVENTION The present invention has as an objective an improved process for the preparation of a compound derived from aspart and that is useful as a sweetening agent. More precisely, the present invention aims at a process for the preparation of an N-substituted derivative of aspartame, namely the N- (N- (3,3-dimethylbutyl) -L-X 1-methyl ester -particular) -L-phenylalanine, of the formula: This compound is a very powerful sweetener since it has, on a ponderable basis, a sweetness imparting power that is at least 50 (fifty) times higher than that of aspartame and about 10,000 (ten thousand) times higher than that of sucrose (table sugar). Sweeteners are mainly intended for human food consumption, it is necessary to prepare, for their preparation, procedures that allow obtaining high purity products, practically free from REF: 23313 pollutants or degradation products. Furthermore, in order to be used on an industrial scale, these procedures must be mastered preferentially to be reproducible and of a relatively low cost. Insofar as the compound, whose preparation process is the objective of the present invention, is a derivative of aspartame, it seems advantageous to investigate a synthesis route using aspartame as an initial compound or as an intermediate. Aspartame, in fact, is currently the most used synthetic sweetener, responding to the standards required for food use; In addition, its industrial preparation is perfectly dominated with a relatively low cost, despite its dipeptid structure. However, it is known that it is relatively difficult to use aspartame as an initial product or as an intermediate product in an industrial synthesis. Aspartame, in fact, has a relatively low solubility in most organic solvents, generally less than a few grams per liter. On the other hand, if the solubility of aspartame is higher in aqueous media, its stability is, however, relatively low in these media. In addition, all attempts to increase the temperature in order to improve the solubility of aspartame aggravate its degradation processes.

Under these conditions, the present invention aims to solve the technical problem consisting in the provision of an improved process for the preparation of the aforementioned derivative of aspartame, which can be carried out in a simple and reproducible manner, on an industrial scale, to a relatively low sales price, and that uses aspartame as an initial product or as an intermediate product. It has been discovered, and this is what constitutes the basis of the present invention, that it is possible to obtain the N-alkylated derivative of aspartame, mentioned above, from aspartame, in a single step, and this with an extremely high yield and a very high purity, compatible with the use of this compound in the food field. According to the present invention, the process for the preparation of N- (N- (3, 3-dimethylbutyl) -L-0-aspartyl) -L-phenylalanine 1-methyl ester of the formula: CH 3 H CH3 - is characterized in that a solution of aspartame and 3,3-dimethylbutyraldehyde is treated at room temperature, with hydrogen, at a pressure less than or equal to 1 bar (0.1 mPa), in the presence of a catalyst based on platinum or palladium. In an advantageous form of application of the invention, the catalyst mentioned above is chosen from the group comprising platinum on activated carbon, palladium on activated carbon, platinum black and palladium black. In a particularly advantageous form, the hydrogenation is carried out in the presence of 5% platinum on activated carbon, at a relative pressure of 1 bar, or in the presence of 10% palladium on activated carbon, at atmospheric pressure or at a relative pressure of 1 bar. In a presently preferred application of the invention, the solution of aspartame and 3,3-dimethylbutyraldehyde, is a hydroalcoholic solution of pH 4.5 to 5, which is obtained by mixing a solution of acetic acid 0.1M with methanol, the concentration of aspartame that is found in this solution comprises between 50 and 60 g / L, and that of 3,3-dimethylbutyraldehyde, between 20 and 30 g / L. In an advantageous aspect of the invention, the formed product is purified by means of precipitation and filtration, after the vacuum removal of the alcoholic part of the solvent. The process according to the invention thus allows obtaining, by means of reductive alkylation of aspartame on the N side, a very pure sweetening compound, with a very high yield.

Numerous examples of reductive alkylation on the N side that make use of the hydrogen associated with the catalysts are described in the literature (see, for example, the review of PN Rylander, "Catalytic Hydrogenation in Organic Syntheses", Academic Press, San Diego, 1993, pp. 165-174). The application of this general technique to the process described in the present invention has hitherto been possible only by selecting the catalysts and adopting the very specific experimental conditions which are only conducted with the high analytical purity necessary for the alimentary use of the compound that is the object of the process of the present invention. In fact, it has been found that the quality of the desired product depends very strictly on the experimental conditions used during the application of the process. The nature of the catalyst, and to a lesser extent the duration and pressure of hydrogenation, the nature of the reaction medium and its pH are thus revealed as essential parameters. It should be noted that, in the case of hydrogenation reactions on an industrial scale, the conditions that allow to significantly reduce the reaction time up to a duration of the order of a few hours, always maintaining a satisfactory yield and falling into the domains of lower pressures or equal to 1 bar (0.1 mPa), are very sought after. While the reaction is generally accelerated, the use of high pressures is generally not desired for reasons of safety and for the cost of the material. The hydrogenation catalysts used in the context of the present invention act unexpectedly, on the one hand, at pressures relatively less than or equal to 1 bar (0.1 mPa) and, on the other hand, with durations equal to or less than 24 hours. Monitoring the progress of the reaction by means of a sample and evaluating the product formed using high performance liquid chromatography (HPLC) allows those skilled in the art to easily determine the duration of the hydrogenation most appropriate for the conditions used. Among the possible catalysts, those based on platinum or palladium dispersed on activated carbon or in the form of platinum or palladium black, have been shown to be particularly advantageous. It has been observed that other catalysts, such as nickel on silica (Aldrich No. 20,878-7), nickel on silica and alumina (Aldrich No. 20,877-9), Raney nickel (Aldrich No. 22,167-8), ruthenium black (Aldrich No. 32,671-2), ruthenium on carbon (Aldrich No. 28,147-6), palladium hydroxide on carbon (Aldrich No. 21,291-1), palladium oxide (Aldrich No. 20,397-1), rhodium black (Aldrich No. 26,734-1), rhodium on carbon (Aldrich No. 33,017-5) or rhodium on alumina (Fluka No. 83720) also allow the preparation of the compound of the invention. However, these catalysts have shown that they are less active and that they especially need higher hydrogen pressures or which are less selective and which lead in particular to a reduction of the aromatic ring of aspartame or its desired N-alkylated derivative. It has also been observed that higher hydrogenation pressures, or longer hydrogenation times than those used in the process of the invention, can also affect the performance and quality of the finished product. It is the same for the amounts of catalyst used, which also have a special influence on the hydrogenation time. The catalysts selected in the context of the present invention are particularly effective at concentrations between 5 and 20%, with respect to aspartame. The hydroalcoholic solution of pH 4.5-5, used in the process of the invention, proves particularly advantageous and allows a rapid dissolution of the reagents and favors during the treatment the separation of the desired product in a state of high purity. The use of a purely aqueous reaction medium, in effect, causes the precipitation of the product and its aggregation with the catalyst. The duration of the reaction is then longer and the separation of the catalyst becomes difficult. It has also been shown that a pH close to a value of 4.5 to 5, for the reaction medium, accelerates the reaction, significantly reducing the degradation processes of aspartame. In summary, the choice of very specific catalysts that operate at low hydrogen pressures in a often very short time, at room temperature and in hydroalcoholic medium of pH 4.5 to 5, allow to respect the stability and solubility restrictions linked to the aspartame. The very high yields obtained in these conditions facilitate obtaining a product with a very high quality which is also easily recovered by a simple precipitation after the removal of the alcoholic part of the reaction solvent. The present invention will be described more fully with the help of the following examples, which should not be considered as limiting the invention.

EXAMPLE 1 In a reactor equipped with an agitation that allows to assure a good transfer of the gaseous hydrogen in the liquid phase, with stirring and in the following order: 60 cm 3 of an aqueous solution of 0.1 M acetic acid, 1 g of 5% platinum on activated carbon (Aldrich product No. 33.015-9: platinum on activated carbon, wet, Degussa, type F101 RA / W, Pt 5%, 2.55 g of 3, 3-dimethylbutyraldehyde, 30 3 cm of methanol and 5 g of aspartame. After having purged the reactor by means of a nitrogen stream, the mixture is subjected to a hydrogenation at the relative pressure of a bar (0.1 mPa) and at room temperature. The development of the reaction is controlled by taking a crude sample and dosing the product formed by high performance liquid chromatography (HPLC). The concentration of the desired product is determined by comparison with a standard curve, established above. After 2 hours of hydrogenation, the formation of 100% of the expected product is observed. The reaction is then interrupted by purging the reactor by a stream of nitrogen and separating the catalyst by filtration on a fine filter (0.5 microns). If necessary, the filtrate is adjusted to pH 5 by the addition of a few drops of a 1N sodium hydroxide solution. The methanol is then removed by evaporation in vacuo. The temperature is kept below 40 ° C. A white solid precipitates quickly. The mixture is then stirred for a few hours at room temperature to complete the precipitation. The product is separated by filtration, dried and washed with approximately 50 cm of hexane. Finally, 4.4 g of the 1-methyl ester of N- (N- (3, 3-dimethylbutyl) -L-O-aspartyl) -L-phenylalanine (69% yield) in the form of a white powder of high purity (greater than 98% by HPLC).

EXAMPLE 2 Using the same apparatus, the same solvent and the same reagents, at the same concentrations as those described in Example 1, but using as catalyst 1 g of 10% palladium on activated carbon (product Fluka No. 75990: Palladium on charcoal, 10% Pd), carrying out the hydrogenation at a relative pressure of 1 bar (0.1 mPa), always at room temperature, the reaction is stopped after 2 hours (96% of the product formed). After purification by precipitation, following the protocol described in Example 1, 4.3 g of the expected product are obtained (yield 68%) in the form of a white powder of a high purity (greater than 98%, by HPLC).

EXAMPLE 3 Using the same apparatus, the same solvent and the same reagents, at the same concentrations as those described in Example 1, but using as catalyst 1 g of 10% palladium on activated carbon (product Fluka No. 75990: Palladium on Activated charcoal, 10% Pd) Hydrogenation is carried out at atmospheric pressure, always at room temperature, the reaction is stopped after 24 hours (97% of the product formed). After purification by precipitation, following the protocol described in Example 1, 4.3 g of the expected product are obtained (yield 68%), in the form of a white powder, with a very high purity (greater than 98%, by HPLC).

EXAMPLE 4 Using the same apparatus, the same solvent and the same reagents, at the same concentrations as those described in Example 1, but using as catalyst 1 g of platinum black (product Aldrich No. 20,591-5: Platinum Black) , the hydrogenation is carried out at atmospheric pressure, always at room temperature, the reaction is stopped after 1 hour (96% of the product formed). After purification by means of precipitation, following the protocol described in Example 1, 4.4 g of the expected product are obtained (yield 69%), in the form of a very pure white powder (greater than 98%, by means of HPLC).

EXAMPLE 5 Using the same apparatus, the same solvent and the same reagents, at the same concentrations as those described in Example 1, but using as catalyst 1 g of palladium black (product Aldrich No. 20,583-4: Palladium black) , the hydrogenation is carried out at atmospheric pressure, always at room temperature, the reaction is stopped after 16 hours (98% of the product formed). After purification by precipitation, following the protocol described in Example 1, 4.4 g of the expected product (69% yield) are obtained in the form of a very pure white powder (purity higher than 98% by HPLC). «. The purity of the compound prepared following the process of the invention is controlled by means of the classical thin layer chromatography techniques; infrared spectrometry; ultraviolet spectrometry; high performance liquid chromatography (HPLC); thermal analysis; rotating power; nuclear magnetic resonance and centesimal analysis. The physical criteria obtained for the compound prepared according to the invention are those given below. Amorphous white powder, odorless, non-hygroscopic. Molecular formula: C20 30N2 ° 5 * Molecular weight: 378.4 Water content (Karl Fischer method): 3% to 6%. Thin layer chromatography: Silica gel 60 F254 on aluminum sheets (Merck No. 5554); eluent: butanol-acetic acid-water (8: 2: 2); revealed with ninhydrin; Rf: 0.54. Infrared spectrum (KBr) cm "1: 3587 (HOH); 3444, 3319 (NH), 3028 (CH), 2957, 2867 (CH), 1733 (COOCH ..), 1690 (CONH), 1594 (COO "), 1565, 1541, 1440, 1414, 1390, 1368, 1278, 1245, 1218, 1173, 1119, 999, 758, 701 (CH). Ultraviolet spectrum: maximum at 214 nm and 257 nm. High resolution liquid chromatography on Merck column type "Lichrospher 100 RP-18 and with cap on one end" (Lichrospher 100 RP-18 endcapped); length 244 mm; diameter 4 mm; eluent: 65 mM ammonium acetate-acetonitrile (65:35); elution speed 1 ml / min; detector: refractometer; time '** retention 7.7 min. Differential thermal analysis from 40 C to 350 C, at 10 ° C / min: melting point 84 ° C, without decomposition below 200 ° C. Rotary power: (OC) D20 = -46.5 ° +/- 1.5 (c = 2, methanol). Nuclear magnetic resonance spectrum (H, 200 MHz, DMSO-d6) 0.81 (s, 9 H), 1.28 (m, 2 H), 2.38 (m, 4 H), 2.9 (m, 2 H), 3.44 (m , 1 H), 3.62 (s, 3 H), 4.55 (m, 1 H), 7.22 (m, 5 H), 8.54 (d, 1 H). centesimal analysis: found (theoretical for 4.5% of water): C 60.51 (60.73); H 7.86 (8.12); N 7.07 (7.08); O 23.62 (24.04).

The compound prepared following the procedure described above and illustrated is particularly useful for sweetening a variety of products, in particular beverages, foods, confectionery, confectionery, chewing gums, hygiene products and toiletries. , as well as cosmetic, pharmaceutical and veterinary products.

It is noted that, in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.

Claims (8)

1. A process for the preparation of the N- (N- (3, 3-dimethylbutyl) -L-α-aspartyl) -L-phenylalanine 1-methyl ester of the formula: characterized in that a solution of aspartame and 3,3-dimethylbutyraldehyde is treated, at room temperature, by means of hydrogen at a relative pressure equal to or less than 1 bar (0.1 mPa), in the presence of a catalyst based on platinum or palladium.

2. The method according to claim 1, characterized in that the catalyst is selected from the group containing platinum on activated carbon, palladium on activated carbon, palladium black and platinum black.

3. The process according to claim 1, characterized in that the hydrogenation is carried out in the presence of 5% platinum on activated carbon, at a relative pressure of 1 bar.

4. The process according to claim 1, characterized in that the hydrogenation is carried out in the presence of 10% palladium on activated carbon at the relative pressure of 1 bar, or at atmospheric pressure.

5. The process according to claim 1, characterized in that the hydrogenation is carried out in the presence of platinum black or palladium black at atmospheric pressure.

6. The process according to claim 1, characterized in that the solution of aspartame and 3,3-dimethylbutyraldehyde is a hydroalcoholic solution of pH 4.5 to 5 which is obtained by mixing a solution of 0.1 M acetic acid and methanol.

7. The process according to claims 1 to 6, characterized in that the concentration of aspartame in the hydroalcoholic solvent is between 50 and 60 g / L and the concentration of 3,3-dimethylbutoraldehyde is between 20 and 30 g / L.

8. The process according to claims 1 to 7, characterized in that the product formed is purified by means of precipitation and filtration, after the vacuum removal of the alcoholic part of the solvent.