Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-05-18
2003-11-04
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S024000, C560S032000, C560S033000
Reexamination Certificate
active
06642406
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the synthesis of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester (neotame) using L-&agr;-aspartyl-L-phenylalanine 1-methyl ester (aspartame) precursors. This method of producing neotame results in high purity and is more simple and more economical than the conventional preparation of neotame.
2. Related Background Art
N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester (neotame) is a high potency dipeptide sweetener (about 8000× sweeter than sucrose) that has the formula
The chemical synthesis of neotame is disclosed in U.S. Pat. Nos. 5,480,668, 5,510,508, 5,728,862 and WO 00/15656, the disclosure of each of which is incorporated by reference herein.
U.S. Pat. Nos. 5,510,508 and 5,728,862 describe the synthesis of neotame by hydrogenation of a mixture of aspartame and 3,3-dimethylbutyraldehyde with a catalyst such as Pd on carbon. This synthesis is represented by the following equation.
The aspartame used in this synthesis is produced by its precursors. For example, aspartame may be produced by neutralization of aspartame hydrochloride followed by crystallization as described in U.S. Pat. No. 5,266,719, the disclosure of which is incorporated by reference herein. Such a neotame process requires the reaction of pure isolated aspartame with the aldehyde to produce neotame. Therefore, it would be economically advantageous to use aspartame precursors directly in neotame synthesis without having to first isolate aspartame.
International Patent Publication No. WO 00/15656 attempts to eliminate some of these complicated process steps. WO 00/15656 describes the formation of neotame by hydrogenation of a mixture of 3,3-dimethylbutyraldehyde and Z-aspartame (N-benzyloxycarbonyl-L-&agr;-aspartyl-L-phenylalanine-1-methyl ester) in a methanolic solvent.
WO 00/15656 discloses that the neotame obtained by this method has a purity as low as 87% with significant amounts of known and unknown impurities.
Since neotame is mainly employed in foods for human consumption, it is extremely important that neotame exist in a highly purified state. Any impurity >0.1% must be structurally characterized and subjected to safety studies. In this regard, it is clear that the neotame produced by the method of WO 00/15656 is not acceptable with respect to purity.
Thus, it is clear that there is a need to economically and efficiently produce pure N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester.
SUMMARY OF THE INVENTION
The present invention relates to the efficient, low cost and high purity synthesis of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester (neotame). According to one embodiment of the present invention, neotame is synthesized by reacting an acid salt of aspartame and 3,3-dimethylbutyraldehyde in a solvent or a mixture of solvents under hydrogenation conditions with a catalyst. The acid salt of aspartame may be an isolated compound or its wet cake. In certain preferred embodiments, hydrobromic, sulfuric, phosphoric, citric, acetic or hydrochloric acid salts of aspartame are employed.
In a second embodiment of the present invention, neotame is synthesized by hydrogenating a mixture of N-protected aspartame and 3,3-dimethylbutyraldehyde in a solvent or a mixture of solvents with a catalyst. The protecting groups are those that can be cleaved by hydrogenolysis. They include, without limitation, carbamate, amides, benzylidenes, benzyl and silyl.
DETAILED DESCRIPTION
The present invention relates to the synthesis of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester (neotame) by hydrogenation of a mixture of 3,3-dimethylbutyraldehyde and a precursor of L-&agr;-aspartyl-L-phenylalanine 1-methyl ester (aspartame) with a catalyst. More specifically, an acid salt of aspartame (isolated or generated in situ) or protected aspartame is used to produce neotame, thereby eliminating the need to isolate aspartame prior to its combination with 3,3-dimethylbutyraldehyde.
According to the first embodiment of the present invention, N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester is synthesized by reacting an acid salt of L-&agr;-aspartyl-L-phenylalanine 1-methyl ester and 3,3-dimethylbutyraldehyde in a solvent or a mixture of solvents under hydrogenation conditions, i.e., in the presence of hydrogen, with a catalyst. Optionally, the acid salt of L-&agr;-aspartyl-L-phenylalanine 1-methyl ester is pretreated with a base; alternatively, a base is included in the reaction mixture.
Suitable acid salts of aspartame include, without limitation, hydrobromic, sulfuric, phosphoric, citric, acetic and hydrochloric acid salts of L-&agr;-aspartyl-L-phenylalanine 1-methyl ester. The acid salt of aspartame used in the present inventive process can be a wet cake or a dry cake. The acid salt of aspartame can also be used in situ from its precursors by the acidic hydrolysis of an N-protected aspartame, for example, by treatment of N-formyl aspartame, N-BOC aspartame or other N-protected aspartame with HCl or another acid. The N-protected aspartame may be, without limitation, acetyl, benzoyl, benzyloxycarbonyl, (p-chlorobenzyl)oxycarbonyl, (p-bromobenzyl)oxycarbonyl, (p-nitrobenzyl)oxycarbonyl, tert-butyloxycarbonyl, formyl, (p-methoxybenzyl)oxycarbonyl (MOZ) or p-toluene sulfonyl (Ts). One of ordinary skill in the art would readily recognize that both the meta- and ortho-forms of the above-listed para-groups are also suitable for use in the present invention.
Generally the concentration of the acid salt of aspartame in the solvent is in a range of about 2% to about 20%, more preferably about 7% to about 15%.
The acid salt of aspartame is optionally pre-treated with a base. Suitable bases include, without limitation, sodium carbonate, potassium carbonate and ammonium hydroxide. Alternatively, a base may be included in the reaction mixture. The base may be used in amount of about 0.80 to about 1.2 equivalent of the acid in the acid salt of aspartame.
According to the second embodiment of the present invention, N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester is synthesized by reacting an N-protected L-&agr;-aspartyl-L-phenylalanine 1-methyl ester intermediate, 3,3-dimethylbutyraldehyde and a catalyst in a solvent or a mixture of solvents in the presence of hydrogen to produce N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester.
The N-protected aspartame suitable for hydrogenolysis use in the present invention comprises a protecting group. Suitable protecting groups include, without limitation, carbamates such as benzyloxycarbonyl, (p-chlorobenzyl)oxycarbonyl, (p-bromobenzyl)oxycarbonyl,(p-methoxybenzyl)oxycarbonyl (MOZ), (p-nitrobenzyl)oxycarbonyl, formyl, benzyl and silyl.
The N-protected aspartame used in the present inventive process can be a wet cake or a dry cake. Protected aspartame can be prepared by any known chemical or enzymatic method.
Generally the concentration of the N-protected aspartame in the solvent is in a range of about 2% to about 20%, more preferably about 7% to about 15%.
Solvents suitable for use in either embodiment of the present invention include, without limitation, ethanol, ethyl acetate, acetonitrile, dioxane, methanol, isopropanol, isobutyl methyl ketone, tetrahydrofuran, cyclohexane, toluene, dimethylformamide (DMF), water and mixtures thereof. The solvent can be added to a dry cake of an acid salt of aspartame or N-protected aspartame. Alternatively, the solvent may be used in situ in the formation of an acid salt of aspartame or N-protected aspartame, or it may be added to a reaction mixture.
The catalyst suitable for use in either embodiment of the present invention may be selected from catalysts based on palladium or platinum including, without limitation, platinum on activated carbon, palladium on activated carbon, platinum black or palladium b
Guo Zhi
Prakash Indra
Schroeder Steve
Wachholder Kurt L.
Fitzpatrick ,Cella, Harper & Scinto
Richter Johann
The NutraSweet Company
Zucker Paul A
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