Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-12-20
2001-05-15
Nazario-Gonzalez, Porfirio (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06232497
ABSTRACT:
This invention relates to a method for producing very pure and largely anhydrous pyruvates, new kinds of pyruvates, and the use thereof.
Salts of pyruvic acid (pyruvates) are known to have valuable physiological, therapeutic and dietetic properties. Pyruvates, especially calcium pyruvates, are used to enhance endurance and strength in the field of sport, and to reduce weight and body fat in the field of health care, where they are also used as protective substances for body cells and tissues (in particular for cardiovascular, hepatic, nephrotic, peritoneal and neuronal tissues), as a substance which inhibits the formation of free radicals and also serves as a free-radical scavenger in body cells and tissues (including synovial tissues). In addition, pyruvates are used as food supplements, wound-healing agents and for the treatment of kidney diseases (acute kidney failure and nephrolithiasis).
Calcium and magnesium pyruvates, in particular, have become established as harmless agents suitable for therapeutic purposes and as food supplements.
There are only two methods which have been disclosed so far as prior art for producing calcium pyruvates. According to the article published by K. Jowanowitsch in “Monatshefte” No. 6, pp. 467-476 (1885), tartaric acid in glycerin is dehydrated and decarboxylated to a glycidyl pyruvate, which subsequently reacts with lime in aqueous solution to form calcium pyruvate. As was established by proceeding the examples of this publication, this process does not result in the formation of calcium pyruvates but of polymeric pyruvic acid derivatives.
According to the French patent 1 465 432, calcium pyruvate is obtained by neutralizing pyruvic acid with calcium carbonate, hydroxide or oxide in water. The disadvantage of this method is the fact that only impure and unstable calcium pyruvates are obtained, which contain more than 2.5 mol water of crystallization and occur in the form of 2,2-dihyroxypropionate ions. These reaction products usually contain little calcium pyruvate and comparatively large quantities of by-products, since the pyruvic acid or pyruvate ions react by ways of aldol addition or aldol condensation to form acyclic or cyclic dimers and polymers of pyruvic acid. As one result they do not have a sufficiently long shelf life to be used as therapeutic agents or food supplements, or for special physical or solid-state applications. Among the acyclic compounds, special mention must be made of para-pyruvic acid (4-hydroxy-4-methyl-2-oxoglutaric acid) and its salts, and of the higher aldol addition products. As by-products oxalic and methyl succinic acid may also be formed.
By way of lactonization, ketalization and other reactions, the acyclic pyruvic acid polymers can form cyclic compounds such as 2-hydroxy-2-methyl-4-oxoglutaric acid-5-lactone and derivatives of trimesic acid, isophthalic acid and pyran tricarboxylic acid (Beilstein, Hauptwerk Vol. 3, pp. 608-613; 1. Ergänzungswerk, pp. 217-219; 2. Ergänzungswerk, pp. 393-401; 3. Ergänzungswerk, pp. 1146-1156; 4. Ergänzungswerk, pp. 1505-1510). These by-products can be formed in a similar way during storage of calcium pyruvates containing more than 2.5 mol of water of crystallization.
Calcium pyruvates disclosed in the prior art are thus unsuitable for therapeutic uses (as free-radical scavengers, for cell protection, obesity, etc.) or as a food supplement, because during production and storage of these pyruvates by-products and decomposition products of pyruvic acid and its salts are formed which can be physiologically incompatible or even toxic. For the same reasons, the specifications for their preparation cannot be transferred to other alkaline earth metals.
Because of the formation of by-products during the production of alkali metal and alkaline-earth metal pyruvates according to prior art techniques until now the syntheses of rubidium or cesium pyruvate was not possible (cf. G. Gattow, W. Rach, Z. anorg. allg. Chem. 592 (1988), 160-164). Strontium and barium pyruvate, likewise, either cannot be prepared by prior art techniques, or else are not sufficiently pure.
Methods for preparing sodium and potassium pyruvates are also state of the art, but the resulting pyruvates are usually impure and therefore unstable and of low storage stability.
The object of this invention was thus to develop a method for producing alkali metal and alkaline earth metal pyruvates which does not have the aforementioned disadvantages of the prior art but yields products which have a long shelf life, are of high purity and contain a minimum of toxicologically harmful by-products.
This object was established according to the invention by reacting salts of acidic organic compounds selected from organic acids such as carboxylic acids or of acidic organic keto or hydroxy compounds containing a cation selected from the group comprising Li, Na, K, Rb, Cs, Mg, Sr and Ba, or mixtures of these salts, with pyruvic acid at a temperature ranging from −20 to +120° C., if necessary in the presence of a diluent or solvent.
Surprisingly, it was found that in this way high-purity alkali metal and alkaline earth metal pyruvates can be prepared, which have little water of crystallization and/or are largely anhydrous. The alkali metal and alkaline earth metal pyruvates obtained have a low percentage of by-products, especially of para-pyruvates. Preferably, the para-pyruvate content is ≦0.8%, more preferably≦0.2%. Alkali metal and alkaline earth metal pyruvates prepared in this way are also thermostable and satisfy the requirement of a very long shelf life. The extent to which this applies was surprising, because pyruvic acid is a relatively unstable compound and because hitherto-known alkali metal and alkaline earth metal pyruvates decompose to dimeric and polymeric derivatives of pyruvic acid. It was found in addition that the alkali metal and alkaline earth metal pyruvates disclosed in the invention exhibit valuable biological, medical and/or interesting physical or solid-state properties.
According to the method of this invention, therefore, defined alkali metal and alkaline earth metal salts of organic acids or acidic organic keto or hydroxy compounds are reacted with pyruvic acid at a temperature ranging from −20 to +120° C., preferably +10 to +60° C. Suitable organic acids include, eg, aliphatic monocarboxylic acids which may be substituted, eg, with OH—, CO—, CN—, Cl— or Br groups, and/or may be unsaturated. Formic acid, acetic acid, propionic acid, butyric acid and lactic acid are examples of such monocarboxylic acids. For the method of the invention, use can also be made of aliphatic di- and tricarboxylic acids which may be unsaturated and/or substituted, eg, with OH— groups. Citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid and malic acid are examples of such acids. Instead of organic acids, it is also possible to use acidic organic keto or hydroxy compounds, for example ascorbic acid. These organic salts can be used in the anhydrous form, as hydrates or as wet products.
According to the method of the invention, the pyruvic acid, too, can be used optionally in the anhydrous form, as an aqueous solution, or dissolved in a solvent or diluent. The invention additionally provides for the production of the pyruvic acid as an intermediate, for example by reacting an alkali metal pyruvate such as sodium or potassium pyruvate with an inorganic acid such as sulfuric or hydrochloric acid at a temperature ranging from −20 to +90° C., preferably −10 to +60° C.
Suitable solvents or diluents for the method of the invention are water and/or organic solvents such as alcohols (methanol, ethanol, isopropanol, cyclohexanol), ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane), ketones (acetone, methylethyl ketone, cyclohexanone), esters (methyl acetate, ethyl acetate, ethyl formate), organic acids (formic, acetic, propionic, lactic and pyruvic acids), nitriles (acetonitrile), aliphatic (pentane, hexane, cyclohexane) and aromatic hydrocarbons (toluene). It is
Fulbright & Jaworski LLP
Nazario-Gonzalez Porfirio
SKW Trostberg Aktiengesellschaft
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