Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-11-17
2002-10-15
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S040000, C548S334100
Reexamination Certificate
active
06465677
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to an improved method for the preparation of an N-alkylated aspartame derivative, which is a particularly useful sweetening agent.
2. Related Background Art
N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester, or neotame, having the formula below, is a highly intense non-nutritive sweetening agent useful to impart sweetness to a wide variety of food products.
This sweetener, disclosed in U.S. Pat. No. 5,480,668, is approximately 8,000 times as sweet as sucrose, on a weight basis. Thus, very small quantities of this sweetening, agent may be used to produce foods and food products that are equi-sweet tasting to presently available high caloric food products.
Several syntheses of neotame using reductive alkylation of aspartame and 3,3-dimethylbutyraldehyde have been reported. U.S. Pat. No. 5,480,668 discloses a method of adding the 3,3-dimethylbutyraldehyde to a mixture of aspartame and reducing agent in methanol. Sodium cyanoborohydride is disclosed as a useful reducing agent. U.S. Pat. No. 5,510,508 discloses a method using hydrogen at 1 bar or less in the presence of a platinum or palladium catalyst as a reducing agent. In this method, a pH 4.5-5 aqueous-alcoholic solution of aspartame and, 3,3-dimethylbutyraldehyde was treated at room temperature with the reducing agent. The product was purified by precipitation and filtration after evaporation of the alcohol from the solution.
U.S. Pat. No. 5,728,862 describes a method comprising treating a solution of aspartame and 3,3-dimethylbutyraldehyde, in an organic solvent with hydrogen in the presence of a catalyst as a reducing agent. After removal of the catalyst, water was added to form an aqueous/organic solvent solution containing about 17% to about 30% of the organic solvent, by weight, from which the neotame was obtained by precipitation and filtration.
In summary, the preparation of neotame by reductive alkylation of aspartame and 3,3-dimethylbutyraldehyde may proceed by addition of a reducing agent to an aspartame/3,3-dimethylbutyraldehyde mixture or addition of 3,3-dimethylbutyraldehyde to an aspartame/reducing agent mixture, typically in methanol or aqueous methanol. Useful reducing agents include hydrogen in the presence of a palladium or platinum catalyst and hydride reducing agents, especially borohydride reducing agents. However, each of these methods is accompanied by the formation of several impurities, as well as recovery of unreacted starting materials. Since sweetening agents are primarily used in foods for human consumption, it is extremely important that such sweetening agents be produced using methods which provide a high purity product.
Accordingly, it would be desirable to develop very efficient and cost-effective methods of preparing high-purity neotame from readily available or readily obtainable materials.
SUMMARY OF THE INVENTION
This invention relates to the synthesis of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester (neotame) via the reduction of a novel imidazolidinone intermediate.
The method of this invention comprises the steps of reducing at least one reactant selected from (i) &agr;-methyl hydrogen-D-2-(2,2-dimethylpropyl)-5-oxo-&agr;-L-(phenylmethyl)-1,4(L)-imidazolidine diacetate (trans imidazolidinone) having the formula:
(ii) &agr;-methyl hydrogen-L-2-(2,2-dimethylpropyl)-5-oxo-&agr;-L-(phenylmethyl)-1,4(L)-imidazolidine diacetate (cis imidazolidinone) having the formula:
(iii) an imine having the formula:
or (iv) mixtures thereof to form N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester. In a preferred embodiment of the invention, the imidazolidinone intermediate is formed by the reaction of aspartame and 3,3-dimethylbutyraldehyde. This invention also relates to the novel imidazolidinones used in the method of this invention.
DETAILED DESCRIPTION OF THE INVENTION
Aspartame I reacts with 3,3-dimethylbutyraldehyde (II) to form neotame (III) under reductive alkylation reaction conditions, as illustrated in Scheme I, below.
Aspartame (I) and the butyraldehyde (II) reversibly react to form an imine (IV), also called a Schiff's base, and water. This imine is a condensation reaction product of the aldehyde and aspartame, which may convert back to the starting aldehyde and aspartame on addition of water. Under the reaction conditions specified in the method of this invention, the imine may reversibly cyclize to form a 5-membered imidazolidinone. This imidazolidinone may possess either cis or trans stereochemistry, and undergoes equilibration in solution based on the relative stereochemistry of the 3,3-dimethylbutyryl moiety and the methylene carboxyl moiety at the 2 and 4 positions on the heterocyclic ring. Alternatively, these imidazolidinone isomers may be designated as D- and L-isomers, corresponding to the cis and trans isomers, respectively. Cyclization of the imine provides both cis imidazolidinone (V) and trans imidazolidinone (VI).
According to one embodiment of the method of this invention aspartame (I) may be reacted with 3,3-dimethylbutyraldehyde to form a mixture of imine (IV) and imidazolidinones (V and VI) which are in equilibrium with the starting aspartame (I) and butyraldehyde (II). In the absence of water, the equilibrium balance shifts equilibria formation to the imidazolidinone (V and VI); the presence of water shifts equilibria formation to the hydrolysis products/starting materials aspartame (I) and butyraldehyde (II). Formation of imidazolidinone will occur in both the presence or absence of water. However, use of reaction conditions that favor formation of the imidazolidinone by decreasing the water content of the reaction mixture are preferred. For example, use of drying agents or chemical reagents that react with water irreversibly will shift the reaction toward formation of imidazolidinone.
Advantageously, it has been discovered that the imidazolidinone possesses limited solubility in the solvents and solvent mixtures used in the method of this invention. Removal of imidazolidinone by precipitation of the imidazolidinone from the reaction mixture is another way of shifting equilibrium conditions to favor formation of the imidazolidinone. Solid imidazolidinone may be readily isolated from the reaction mixture by filtration, decantation or centrifugation. The solid material produced by the method of this invention may be composed of a mixture of both cis and trans imidazolidinones. The solid imidazolidinone mixture may be used as isolated from the reaction mixture, or may dried.
As indicated above, appropriate selection of the reaction solvent provides for the isolation of solid imidazolidinone by filtration from the reaction mixture. Generally, formation of the imidazolidinone may be conducted in polar protic or polar aprotic solvents. Solvents that are useful for the formation of imidazolidinone according to this invention include C
1
-C
4
alkyl alcohols, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, ethyl acetate and the like, mixtures thereof or aqueous mixtures thereof. Preferably, imidazolidinone formation may be conducted in polar protic or polar aprotic anhydrous solvents. Exemplary preferred solvents include anhydrous C
1
-C
4
alkyl alcohols, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, ethyl acetate and the like, or mixtures thereof. More preferably, imidazolidinone formation may be conducted in anhydrous C
1
-C
4
alkyl alcohol solvents, and most preferably, imidazolidinone formation may be conducted in anhydrous methanol (absolute methanol).
The pH of the reaction mixture for formation of the imidazolidinone mixture is typically between about 4.0 to about 6.0, more preferably, between about 4.5 and 5.5. If desired, the pH of the reaction mixture may be adjusted accordingly.
A preferred manner of obtaining the starting material(s) used in the method of this invention includes condensation of aspartame and 3,3-dimethylbutyraldehyde to form imidazolidinone.
Moore Christine M. V.
Orlovski Vladislav
Prakash Indra
Scaros Mike G.
Chaudhry Mahreen
Hoster Jeffrey M
Killos Paul J.
The NutraSweet Company
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