MXPA00002557A - SWEETENER SALTS OF N-[N-(3,3-DIMETHYLBUTYL) -L-&agr;-ASPARTYL]-L-PHENYLALANINE 1-METHYL ESTER - Google Patents

Abstract

Dipeptide sweeteners are disclosed that are sweetener salts of N-[N-(3, 3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester represented by formula (I), wherein Xm- is a conjugate base derived by deprotonation of an acidic sweetener, preferably saccharin, acesulfame, cyclamic acid and glycyrrhizic acid;and m=n. Also disclosed is a liquid low-calorie sweetener containing such basic salts.

Description

SALTS SWEETENERS OF ESTHER 1-METYLLIC OF N-fN- (3,3-DIMETHYLBUTYL) -L-a-ASPARTIL1-L-PHENYLALANINE BACKGROUND OF THE INVENTION 5 FIELD OF THE INVENTION This invention relates to novel sweeteners. In particular, the invention relates to sweetening salts of the N-alkylated derivative aspartame, 1-methyl ester of N- [N- (3,3-d.methylbutyl) -L- -aspartyl] -L-phenylalanine, ie neotame. The invention also relates to a low calorie liquid sweetener containing said sweetening salts.

RELATED PREVIOUS TECHNIQUE It is known that several N-substituted derivatives of aspartame, such as those described in U.S. Pat. No. 5,480,668, are useful as sweetening agents. In particular, the N-alkylated derivative of aspartame, 1-methyl ester of N- [N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-20-phenylalanine is known as an extremely strong sweetening agent due to its potency sweetener, which on a weight basis, is reported to be at least 50 times that of aspartame and about 10,000 times that of sucrose. ^ g ^! g ^^ ¡£ * ^ iai¡M iuj | MßHÍ | a | H || t ^ mn Because sweetening agents are often used in aqueous solutions and beverages, it is important that they have a dissolving rate acceptable and an effective level of solubility to be feasible from the commercial point of view. U.S. Patent No. 5, 4,031, 258 discloses certain inorganic salts of dipeptide sweeteners that provide improved dissolution and solubility. European Patent Application No. EP 768,041 and Spanish Patent 85-547855 describe salts formed between aspartame and acid sweetening compounds, such as saccharin, cyclamic acid and acesulfame. It is said that these sweetener salts have an improved flavor similar to sucrose. The N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester salts, however, are not described or suggested in any reference. It is known that the physical properties, as well as the stability of aspartame and other peptides can be modified by means of the conversion of its salts. This is described, for example, in U.S. Patent Nos. 4,031, 258 and 4,153,737. U.S. Patent 4,173,737 also discloses low-calorie concentrated liquid sweeteners. Structurally, however, 1-methyl ester of N- [N- (3,3-20-dimethylbutyl) -La-aspartyl] -L-phenylalanine and aspartame differ in that 1-methyl ester of N- [N - (3,3-dimethylbutyl) -La-aspartyl] -L-phenylalanine, a substituent of volumetric neohexyl is present in the nitrogen of the amine. _ ^ - tfiÍ? ta-a ^ í * -h-¡-i-i Aspartame Neotame This structural difference results in serious differences in the physical and chemical properties of these compounds. For example, the melting point of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester is 80 ° C, whereas for aspartame it is 248 ° C. In addition, N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester has a much higher solubility in organic solvents than aspartame, and a much lower solubility in water. It is also known that N- [N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester has greater stability than aspartame under some pH conditions, as described in the US Pat. United States No. 5,480,688. The difference expressed in sweetness between the two compounds is additional evidence of their chemical inequality. Moreover, it is also known that a primary amino group such as that of aspartame (pKa 7.7) generally has a pKa different from those of the secondary amino group such as that of 1-methyl ester of N- [N- (3,3- dimethylbutyl) -La-aspartyl] -L-phenylalanine (pKa 8.1). In addition, it is known that the pKa of an amino acid has a profound impact on food applications (Labuza, T.P. and Basisier, M.W., 1992, "Physical Chemistry of Foods", H.G.

Schwartzber and R.W. Hartel (Eds.), Marcel Dekker, Inc., New York). It is also well known that a secondary amine can not form compounds of the Schiff base type with carbonyl compounds while a primary amine can. In addition, N- [N- (3,3-dimethylbutyl) -L-a-5-aspartyl] -L-phenylalanine-1-methyl ester exhibits a physiologically different behavior than aspartame as exemplified by the dramatic difference in sweetness. These differences are clear indications that the characteristics and properties of one can not suggest those of the other. Although N- [N- (3,3-dimethylbutyl) -L-aspartyl] -10 L-phenylalanine is a highly potent sweetener, it is poorly soluble in water and can cause dusting problems . It would also be convenient to modify and improve the flavor properties of N- [N- (3,3-dimethyl-butyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester to suit a specific application. Therefore, there is a need for ester derivatives 1-N- [N- (3,3-dimethylbutyl) -L- -aspartyl] -L-phenylalanine methyl ester having improved taste, good dissolution properties and solubility in aqueous systems and avoiding problems of dust formation with Frequently found in fine powders. By forming salts with acidic sweeteners, such properties can be achieved.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to dipeptide sweeteners which are sweetening salts of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester which have good dissolution properties and solubility in aqueous systems. In particular, the N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester salts of this invention are represented by the formula Wherein Xm "is selected from the group consisting of conjugated bases derived from deprotonation of acid sweeteners, preferably saccharin, acesulfame, cyclamic acid or glycyrrhizic acid, and m = n, preferably n is 1, 2 or 3. The invention also refers to a low calorie liquid sweetener containing the salts of this invention.

BRIEF DESCRIPTION OF THE DRAWING The figure is a graph comparing the aqueous solution of 1-methyl ester N- [N- (3,3-dimethylbutyl) -La-aspartl] -L-phenylalanine in an objective concentration of 0.05% by weight with equivalent concentrations of neotame, that is, the concentration of the neotame presented in each case is the same, of the acesulfame and of the salts of cyclamate of 1-methyl ester of N- [N- (3,3-dimethylbutyl) -La-aspartyl] - L-phenylalanine.

DETAILED DESCRIPTION OF THE INVENTION This invention is directed to sweetening salts of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester, ie, sweetener salts of neotame. U.S. Patent No. 5,480,668, U.S. Patent No. 5,510,508 and U.S. Patent No. 5,728,862, which describe the preparation of N- [N- (3,3-dimethylbutyl) -l-1-methyl ester -aspartyl] -L-phenylalanine are incorporated by reference herein as if they were fully disclosed. Thus, the starting material can easily be prepared by a person skilled in the art without the need for experimentation. The sweetening salts of this invention can be prepared by adding N- [N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester and an acid sweetening compound to an amount of a solvent effective to dissolve both the N- [N- (3,3-dimethylbutyl) -L- -aspartyl] -L-phenylalanine 1-methyl ester and the acid compound, and then stirring for a time to achieve salt formation. Suitable solvents include ethane, methanol, acetone, acetonitrile, ethyl acetate, water and t-buylmethyl ether. The product of the salt can be recovered by evaporating the solvent in vacuo. The product of the salt can also be recovered by drying by freezing or by spray drying the resulting solution. These salts can also be prepared by adding acid (such as hydrochloric acid, sulfuric acid or phosphoric acid) to a suspension of N- [N- (3,3-dimethylbutyl) -La-aspartyl] -L-phenylalanine 1-methyl ester. and acid salt sweetener (such as sodium saccharin, acesulfame-K potassium salt or sodium cyclamate) in a solvent such as water or alcohol. The sweetening salts of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester prepared under these conditions show no racemisation. The acidic sweetening compounds used in the preparation of the salts of this invention are basically selected from sweetening compounds having a pKa effectively lower than the pKa of the functionality of the N-1-methyl ester of N- [N- (3,3- dimethylbutyl) -L-oc-aspartyl] -L-phenylalanine to result in the formation of the desired salt. Such compounds include, for example, saccharin, acesulfame, cyclohexyl sulfamic acid (hereinafter cyclamic acid) and glycyrrhizic acid. As such, Xm "is the conjugate anion base derived from deprotonation of the acid compound.

In particular, the preferred sweetener salts of this invention include the salts formed between N- [N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester and a Acid sweetener chosen from the group consisting of saccharin, acesulfame, cyclamic acid and glycyrrhizic acid. It is believed that the salts of this invention provide a number of improved properties over those of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester. In particular, the aqueous solubility is increased and the rate of dissolution of the composition is greatly improved. These sweetener salts of neotame are sweet tasting. It is also believed that these salts will have an improved flavor. Thus, N- [N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester salts will be particularly useful in beverage systems, especially since the additional methods or mechanical preparations are diminished or they are not necessary to favor a rapid dissolution as desired in a tabletop sweetener. The salts of this invention can be mixed with known body-forming agents to prepare tablets, powdered sweeteners and granulates using methods well known to those skilled in the art. Another advantage of the salts of this invention is that they do not present the dusting problems associated with N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester. The salts can also be used to prepare a low calorie liquid sweetener by dissolving a high concentration of the sweetening salt of this invention in an aqueous system or alcohol, for example, water, propylene glycol, a water / propylene glycol mixture, ethanol or a water / ethanol mixture. Said low calorie liquid sweetener may find use in food products such as gelatin desserts, fruit flavored drinks, cereal, cake flour, fruit juices, syrups, salad dressings, pet foods, carbonated soft drinks, sweeteners of table and similar. Such utilities are not restrictive since other applications may include cough medicines, tonics and the like. One embodiment of this invention of particular interest contemplates a liquid tabletop sweetener in replacement of sucrose and other known sweeteners. The low-calorie liquid sweetener will generally contain up to about 40% by weight of the N- [N- (3,3-dimethylbutyl) -La-aspartl] -L-phenylalanine 1-methyl ester salt, depending on the concentration , of course, of the desired end use. It is intended that the examples below be an illustration of certain preferred embodiments of the invention, and no limitation of the invention is implied. ; -t? EXAMPLE 1 Acesulfame salt of N- [N- (3,3-dimethylbutyl) -L-a-aspartip-L-phenylalanine 1-methyl ester) Acesulfame (6.30 g, 0.0386 moles) and 1-methyl ester of N- [N- (3,3-dimethylbutyl) -La-aspartyl] -L-phenylalanine (15.31 g, 0.0386 moles) were dissolved in methanol (100 ml ) at room temperature to form a clear solution. Most of the methanol was removed using a rotary evaporator at 33 ° C under vacuum. The residual solvent was removed using a mechanical pump. The yield of the title compound was 20.97 g. Acesulfame salt of N- [N- (3,3-dimethylbutyl) -L- a-aspartyl] -L-phenylalanine 1-methyl ester (0.2 g) was dissolved in water (100 ml) in less than 120 seconds (visual observation). Water content (Karl Fisher): 1.81%. 15 Analysis calculated for C24H35N3? 9S. 0.55H2O: C, 52.27; H, 6. 60; N, 7.62; S, 5.81. Found: C, 52.55; H, 6.50; N, 7.64; S, 5.91. 1 H NMR (DMSO-d 6): d 0.81 (S, 9 H, t-butyl), 1.42 (m, 2 H, -CH 2 -), 1.89 (s, 3 H, CH 3 -C = C), 2.6-3.1 (m, 6H, -CH2-), 3.62 (s, 3H, CH3-O), 4.06 (m, 1 H, -CH-), 4.59 (m, 1 H, -CH-), 5.27 (s, 1 H, HC = C), 7.2-7.3 (m, 5H, phenyl).

EXAMPLE 2 Salt of 1-methyl ester of N-fN- (3,3-dimethylbutyl) -L-a-aspartn-L-phenylalanine Saccharin (7.62 g, 0.0416 moles) and N- [N- (3,3-dimethylbutyl) -L-aspartyl] -L-phenylalanine 1-methyl ester (16.42 g, 0.416 moles) were dissolved in methanol (100 ml) at room temperature to form a clear solution. Most of the methanol was removed using a rotary evaporator at 33 ° C under vacuum. The residual solvent was removed using a mechanical pump. The yield of the title compound was 23.30 g. The saccharin salt of neo-a-aspartame (0.2 g) was dissolved in water (100 ml) in less than 120 seconds (visual observation). Water content (Karl Fisher): 1.16%. Analysis calculated for C27H35N3? 8S. 0.37H2O: C, 57.06; H, 6.34; N, 7.39; S, 5.64. Found: C, 57.23; H, 6.30; N, 7.42; S, 5.69. 1 H NMR (DMSO-d 6): d 0.80 (S, 9 H, t-butyl), 1.42 (m, 2 H, -CH 2 -), 2.5-3.1 (m, 6 H, CH 2 -), 3.62 (s, 3 H, CH 3 -O), 4.05 (m, 1 H, -CH-), 4.58 (m, 1 H, -CH), 7.1-7.7 (m, 9H, phenyl).

EXAMPLE 3 N-fN- (3,3-dimethylbutyl) -L- - aspartyl-L-phenylalanine 1-methyl ester cyclamic acid salt Cyclamic acid (7.33 g, 0.0409 mol) and 1-methyl ester of N- [N- (3,3-dimethylbutyl) -La-aspartyl] -L-phenylalanine (16.22 g, 0.409 mol) were dissolved in methanol (100 ml ) at room temperature to form a clear solution. Most of the methanol was removed using a rotary evaporator at 33 ° C under vacuum. The residual solvent was removed using a mechanical pump. The yield of the title compound was 22.75 g. The cyclic salt of N- [N- (3,3-dimethylbutyl) -L-aspartyl] -L-phenylalanine 1-methyl ester (0.2 g) was dissolved in water (100 ml) in less than 120 seconds (visual observation ). Water content (Karl Fisher): 0.94%. Analysis Calculated for C 26 H 43 N 3 O 8 S.0.29H 2 O: C, 55.47; H, 7. 80; N, 7.46; S, 5.70. Found: C, 55.68; H, 7.72; N, 7.48; S, 5.69. 1 H NMR (DMSO-de): d 0.80 (s, 9H, t-butyl), 1.0-2.0 (m, 12H, -CH2-), 2.5-3.1 (m, 7H, -CH2- and -CH-), 3.62 (s, 3H, CH3-O), 3.90 (m, 1 H, -CH-), 4.57 (m, 1 H, -CH-), 7.1-7.3 (m, 5H, phenyl).

COMPARATIVE EXAMPLE 1 N-rN- (3,3-dimethylbutyl) -L-o: -aspartiH-L-phenylalanine 1-methyl ester solution in water N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine ester (1 - 0.2 g) was dissolved in water (100 ml). The compound completely dissolved in 5-8 minutes (visual observation). The solution of 1.0 g of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester in 100 ml of water required approximately 45 minutes. Other variations and modifications of this invention will be obvious to those skilled in the art. This invention is not limited except as set forth in the following claims. . t -. ^ t - ^^ - M.i -.- ^^? m ^^ M * * ^ ^ ***. ^ .. ^ ¿et ^ j? átS.

Claims (6)

** -t NOVELTY Dg THE INVENTION CLAIMS

1. - A 1-methyl ester salt of N- [N- (3,3-dimethylbutyl) -L- -aspartyl] -L-phenylalanine represented by the formula wherein Xm "is a conjugate base derived from deprotonation of an acid sweetener and m = n 2.- A salt according to claim 1, further characterized in that n is 1, 2 or 3. 3.- A salt in accordance with claim 1, further characterized in that n is 1 and Xm "is a conjugate base derived from deprotonation of an acid sweetener selected from the group consisting of saccharin, acesulfame, cyclamic acid and glycyrrhizic acid. 4. A low calorie liquid sweetener composition comprising a salt of a dipeptide sweetener represented by the formula ^ jj f | ^ ¡| ^^ jgig i gH ' wherein Xm "is a conjugate base derived from deprotonation of an acid sweetener, and m = n, dissolved in a solvent or consumer solvents in a concentration of up to about 40% by weight of the composition to provide a low calorie liquid sweetener of High concentration 5. A low calorie liquid sweetener according to claim 4, further characterized in that the solvent is ethanol 6. A low calorie liquid sweetener according to claim 5, further characterized in that n is 1 and Xm "is a conjugate base derived from deprotonation of an acid sweetener selected from the group consisting of saccharin, acesulfame, cyclamic acid and glycyrrhizic acid. JA ^^ 'a ^^ - -. ^ aütA ^