MXPA00002540A - ACID SALTS OF N-[N-(3,3-DIMETHYLBUTYL)-L-&agr;-ASPARTYL]-L-PHENYLALANINE 1-METHYL ESTER - Google Patents

Abstract

Dipeptide sweeteners are disclosed that are salts of N-[N-(3, 3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester represented by formula (I) wherein X- is selected from the group consisting of Cl?-, HSO4-, H2PO3-, citrate, HCO3-, furmarate, malate, maleiate, tartarate, acetate, benzoate or gluconate. Also disclosed is a liquid low-calorie sweetener container such salts.

Description

SALES 1-METHYL ESTER A-N, N- (3,3-DIMETHYLBUTYL) -L-a-ASPARTIL1-L-PHENYLALANIN BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to novel sweeteners. In particular, the invention relates to acid salts of the N-alkylated derivative of aspartame, N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester, neotame. The invention also relates to a low calorie liquid sweetener containing said salts.

RELATED PREVIOUS TECHNIQUE It is known that several N-substituted derivatives of aspartame, such as those described in the patent of E.U.A. No. 5,480,668 are useful as sweetening agents. In particular, it is known that the N-alkylated derivative of aspartame, 1-methyl ester of N- [N- (3,3-dimethylbutyl) -La-aspartyl] -L-phenylalanine is a very potent sweetening agent since it has been reported that its sweetening power, based on weight, is at least 50 times that of aspartame and approximately 10,000 times that of sucrose.

^ H __ ^ __________ Jl __ &_______ j_t &l __________________________ | __ÍÉl_i Because sweetening agents are often used in aqueous solutions and beverages, it is important that they have an acceptable dissolution index and an effective level of solubility to be commercially viable. . The patents of E.U.A. Nos. 4,029,701 and 4,031,258 disclose certain inorganic salts of dipeptides that provide improved solubility in aqueous solution while maintaining the sweet property of the dipeptide. The patent of E.U.A. 4,448,716 discloses a certain dipeptide sweetener: metal complexes that provide improved dissolution and solubility. The patent of E.U.A. No. 4,153,737 describes concentrated solutions of dipeptide salts in a non-aqueous system (concentrated low-calorie liquid sweetener). However, N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester is not described or suggested. Structurally, N- [N- (3,3-dimethylbutyl) -L-aspartyl] -L-phenylalanine-1-methyl ester and aspartame differ in that 1-methyl N- [N- (3,3- dimethylbutyl) -La-aspartyl] -L-phenylalanine, a substituent of volumetric neohexyl is presented in the nitrogen of the amine.

Aspartame Neotame This structural difference results in serious differences in the physical and chemical properties of these compounds. For example, the melting point of 1-methyl ester of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine is 80 ° C, while for aspartame it is 248 ° C. In addition, N- [N- (3,3-dimethylbutyl) -L-aspartyl] -L-phenylalanine 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- -aspartyl] -L-phenylalanine 1-methyl ester has greater stability than aspartame under some pH conditions, as described in the patent from the USA No. 5,480,688. The difference expressed in sweetness between the two compounds is additional evidence of their chemical inequality. Furthermore, it is also known that a primary amino group such as that of aspartame (pKa 7.7) generally has a pKa different from that of the secondary amino group such as that of N- [N- (3,3-dimethylbutyl) 1-methyl ester. ) -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, TP and Basisier, MW, 1992, "Physical Chemistry of Foods", HG Schwartzber and RW 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-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 the 1-methyl ester of N- [N- (3, 3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine is a highly potent sweetener, is sparingly soluble in water and can give rise to dusting problems. Therefore, there is a need for 1-methyl N- [N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-phenylalanine derivatives which have good dissolution properties and solubility in aqueous systems and which avoid Dust formation problems often found in fine dusts.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to dipeptide sweeteners which are N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester salts which possess good dissolution and solubility properties 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 X "is selected from the group consisting of CI", HSO4"'H2P? 3", citrate, HCO3", furmarate, malate, maleate, tartarate, acetate, benzoate or gluconate The invention also relates to a liquid sweetener low in _____________! __________- -_,. ^^ _.... * .._. _. The calories contained in the acid salts of this invention.

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

DETAILED DESCRIPTION OF THE INVENTION This invention is directed to salts of 1-methyl ester of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine, ie, salts of neotame. The patents of E.U.A. Nos. 5,480,668, 5,510,508 and 5,728,862, which describe the preparation of N- [N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester are hereby included by reference as if they were its entirety Therefore, one skilled in the art can easily prepare the starting material without undue experimentation. The acid salts of this invention can be prepared by first suspending the N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester in a solvent or mixture of solvents. Some Examples of solvents may include water, methanol, acetone, tetrahydrofuran, and the like. The suspension is stirred and an equimolar amount of the desired acid is added slowly to dissolve the N- [N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester and form the salt of this invention . The salt can be recovered by evaporating the solvent, drying by freezing or spray drying the resulting solution. The order of the addition of the sweetener to the acid has not been found to be of importance and can be readily determined by those skilled in the art. The N- [N- (3,3-dimethylbutyl) -L- -aspartyl] -L-phenylalanine 1-methyl acid ester salts prepared under these conditions show no racemization. The addition of excess acid (more than equivalent 1) causes hydrolysis of the methyl ester. The acids used in the preparation of the salts of this invention are typically selected from compounds having a pKa effectively lower than that of the pKa of the secondary amine of N- [N- (3,3-dimethylbutyl) 1-methyl ester) La-aspartyl] -L-phenylalanine to result in the formation of the desired salt. Such compounds include, for example, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, acetic acid, benzoic acid, gluconic acid and carbonic acid. As such, X "is a physiologically acceptable anion selected from the group consisting of CI", HSO4"'H2P03", citrate, HCO3", furmarate, malate, maleate, tartarate, acetate, benzoate or gluconate These ions can be used alone or in combination.

Particularly preferred salts of this invention include the N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine 1-methyl ester hydrochloride, phosphate, sulfate, citrate, hydrobromide and carbonate salts. It is believed that the acid salts of this invention provide a series of improved properties compared to those of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine-1-methyl ester. In particular, the aqueous solubility increases and the dissolution rate of the composition improves a lot. These acid salts of neotame are sweet and it is also believed that these salts have an improved flavor. Therefore, these salts of N- [N- (3,3-dimethylbutyl) -L-aspartyl] -L-phenylalanine 1- methyl ester will be particularly useful in beverage systems, particularly because the methods or mechanical preparations Additional reductions are or are not necessary to provide 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 or granulates using methods well known to those skilled in the art. These salts can also be used to prepare a low calorie liquid sweetener by dissolving a high concentration of the salt of this invention in an aqueous or alcoholic system, for example, water, ethanol, water / ethanol, propylene glycol or propylene glycol / water. Said low calorie liquid sweetener may find utility in food products such as gelatin desserts, fruit flavored beverages, cereal, flours prepared for cake, fruit juices, syrups, salad dressings, pet food, carbonated soft drinks, tabletop sweeteners and the like. Said utilities are not limited since other applications may include cough medicines, tonics and the like. One embodiment of this invention of particular interest contemplates a liquid tabletop sweetener as a substitute for sucrose and other known sweeteners. The low-calorie liquid sweetener will usually contain up to about 40% by weight of the N- [N- (3,3-dimethylbutyl) -La-aspartyl] -L-phenylalanine 1-methyl ester salt, the concentration depending on the concentration , of course, of the desired end use. The following examples are intended to illustrate certain preferred embodiments of the invention, and do not imply limitation of the invention.

EXAMPLE 1 Salt of N-fN- (3,3-dimethylbutyl) -L-a-aspartyl-L-phenylalanine 1-methyl ester hydrochloride N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine-1-methyl ester (25.0 g) was suspended in 150 ml of water. To the stirred suspension was slowly added concentrated hydrochloric acid (5.5 ml, 0.0661 moles). After about 10 minutes all the solid material had dissolved. Then the clear solution was dried by freezing. The resulting product exhibited an aqueous solubility increased greatly compared to the starting material. Yield: 27.34 g of white solid material (99.7%). The hydrochloride salt (1 g) was dissolved in water (100 ml) in 70 seconds.l H NMR (CD3CN) d 0.89 (s, 9H), 1.64 (m, 2H), 3.01 (m, 6H), 3.68 ( s, 3H), 4.16 (t, 1 H), 4.67 (m, 1 H), 7.26 (m, 5H), 8.27 (d, 1 H). Analysis calculated for C2oH31CIN2O5 • H2O: C, 55.48; H, 7.69; N, 6.47; Cl, 8.19. Found: C, 55.95; H, 7.59; N, 6.55; Cl, 8.35.

EXAMPLE 2 Salt of 1-methyl ester phosphate of N-fN- (3,3-dimethylbutyl) -L-a-aspartill-L-phenylalanine N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine-1-methyl ester (10.0 g) was suspended in 100 ml of water. An equimolar amount of 85% phosphoric acid solution was added. After all the solid material dissolved, the solution was freeze dried. The resulting product exhibited an aqueous solubility increased greatly compared to the starting material. Yield: 12.33 g of white solid material (98.0%). The phosphate salt (0.1 g) was dissolved in water (100 ml) in less than 30 seconds (visual observation) and approximately 90 seconds by spectrophotometric analysis. 1 H NMR (CD3CN) d 0.89 (s, 9H), 1.55 (m, 2H), 2.84 (m, 5H), 3.19 (m, 1 H), 3.67 (s, 3H), 4.06 (t, 1 H) , 4.70 (m, 1 H), 7.27 (m, 5H), 8.03 (d, 1 H). Analysis calculated for C2oH33N2O9P • H2O: C, 48.58; H, 7.15; N, 5.67; P, 6.26. Found: C, 48.15; H, 7.08; N, 5.60; P, 6.57.

EXAMPLE 3 N-fN- (3,3-dimethylbutyl) -L-a-aspart-p-L-phenylalanine 1-methyl ester sulphate salt N- [N- (3,3-dimethylbutyl) -La-aspartyl] -L-phenylalanine ester (1-methyl) (25.0 g) was suspended in 100 ml of water and concentrated sulfuric acid (3.67 ml, ). After several minutes of stirring, some of the material remained undissolved. Therefore, 75 ml of acetone was added. The resulting clear solution was stirred for 30 minutes, then the acetone was removed under reduced pressure in a rotary evaporator. The contents of the flask remained a clear solution. Freeze drying of this solution provided a white solid material that exhibits increased aqueous solubility compared to the starting material. Yield: 30.04 g (95%). The sulfate salt (0.1 g) was dissolved in water (100 ml) in less than 20 seconds (visual observation). 1 H NMR (CD3CN) d 0.89 (s, 9H), 1.57 (m, 2H), 2.91 (m, 5H), 3.20 (m, 1 H), 3.68 (s, 3H), 4.15 (t, 1 H), 4.72 (m, 1 H), 7.27 (m, 5H), 7.68 (d, 1 H). Analysis calculated for C2oH32N2? 9S • H2O: C, 48.56; H, 6.94; N, 5.66; S, 6.48. Found C, 48.93; H, 7.02; N, 5.78; S, 6.50.

EXAMPLE 4 Salt of 1-methyl ester of N-rN- (3,3-dimethylbutyl) -L-a-aspartyl-L-phenylalanine N- [N- (3,3-dimethylbutyl) -La-aspartyl] -L-phenylalanine ester (1-methyl) (5.00 g) was dissolved in 75 ml of acetone Citric acid (2.53 g) was dissolved in 50 ml of water , and the acetone solution was added. This formed a clear, colorless solution that was stirred for 1 hour. The acetone was evaporated under reduced pressure. The resulting suspension was dried by freezing to obtain 7.5 g of a white solid material. The citrate salt (0.1 g) was dissolved in water (100 ml) in 90 seconds (visual observation), d (CD3CN) 0.89 (s, 9H), 1.53 (m, 2H), 2.83 (m, 10H), 3.20 (m, 1 H), 3.67 (s, 3H), 4.04 (t, 1 H), 4.21 (m, 1 H), 7.27 (m, 5H), 7.79 (d, 1 H). Analysis calculated for C 26 H 38 N 2 O 12 • H 2 O: C, 53.05; H, 6.86; N, 4.76; Found: C, 53.10; H, 6.88; N. 4.41.

COMPARATIVE EXAMPLE 1 Dissolution of 1-methyl ester of N-fN- (3,3-dimethylbutyl) -L-a-aspartin-L-phenylalanine in water N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine-1-methyl ester (0.05-0.1 g) was dissolved in water (100 mL). The compound completely dissolved in 5-7 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 should not be limited except by what is disclosed in the following claims.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. - A salt of 1-methyl ester of N- [N- (3,3-dimethylbutyl) -L-a-aspartyl] -L-phenylalanine represented by the formula wherein X "is selected from the group consisting of CI", HSO4", H2PO3", citrate, HCO3", furmarate, malate, maleate, tartarate, acetate, benzoate or gluconate 2.- The salt according to claim 1 , further characterized in that X "is CI." 3. The salt according to claim 1, further characterized in that X "is HSO4." 4. The salt according to claim 1, further characterized by X "is H2PO3. 5. The salt according to claim 1, further characterized in that X "is citrate. 6. The salt according to claim 1, further characterized in that X "is HCO3". M_Ü ___________? • M ___ É__Üb? The salt according to claim 1, further characterized in that X "is furmarate 8. The salt according to claim 1, further characterized in that X" is malate. 9. The salt according to claim 1, further characterized in that X is maleate. 10. The salt according to claim 1, further characterized in that X "is tartarate 11. The salt according to claim 1, further characterized in that X" is acetate. 1

2. The salt according to claim 1, further characterized in that X "is benzoate 1

3. The salt according to claim 1, further characterized in that X'is gluconate 14.- A liquid sweetener composition low in calories comprising a salt of a dipeptide sweetener represented by the formula wherein X "is selected from the group consisting of CI", HSO4", H2P? 3_, citrate, HCO3", furmarate, malate, maleate, tartarate, acetate, benzoate or gluconate, dissolved in a solvent or consumable solvents in a concentration up to about 40% by weight of the composition to provide a low calorie liquid sweetener. 15. The low-calorie liquid sweetener according to claim 14, further characterized in that the solvent is ethanol, water, propylene glycol or a mixture thereof. ________ ¡___________ __ ^^^^^^ _ ^ j ||| ^ | Gj ^