MXPA99011864A - Method for producing calcium pyruvates - Google Patents

Abstract

The invention relates to a method for producing calcium pyruvates, wherein calcium salts of organic acids or acid organic keto or hydroxy compounds are reacted with pyruvic acid at a temperature ranging from -20 to +120°C, optionally in the presence of a diluent or a solvent. This enables the production of highly pure calcium pyruvates which can be substantially water-free and exhibit very good storage stability. Said calcium pyruvates are used to increase stamina and vigour in the field of sports, to reduce weight and fat, and as protective substance for body cells and tissues and as substance for inhibiting the formation of free radicals, as well as free radical scavenger in body cells and tissues in health care and as food additive.

Description

METHOD TO PRODUCE CALCIUM PIRUVATES DESCRIPTION OF THE INVENTION This invention relates to a method for producing calcium pyruvates, which is especially suitable for producing very pure anhydride calcium pyruvate salts, as well as with novel calcium pyruvate salts and the use of these , especially as a component of physiologically compatible compositions. It is a known fact that pyruvic acid salts (pyruvates) have valuable dietary, therapeutic and physiological properties. Pyruvates, especially calcium pyruvates, are used to improve stamina and vigor in the field of sports, to reduce weight and body fat in the health field, where it is also used as a protective substance for tissues and body cells (particularly for neuronal, peritoneal, nephrotic, hepatic and cardiovascular tissue) as a substance which inhibits the formation of free radicals and as a substance that removes free radicals in tissues and their body cells (including synovial tissue). Pyruvates are also used as food supplements, wound healing agents and for the treatment of kidney diseases (acute kidney failure and nephritis). Of the pyruvate salts, the potassium and sodium pyruvates, however, are few suitable for therapeutic applications or as food supplements due to their content of sodium and potassium ions. Compared to alkali metal ions, calcium ions do not result in any physiological side effects, which means that calcium pyruvates can be used safely for therapeutic purposes and as a dietary supplement. There are only two methods that have been described so far in the prior art to produce calcium pyruvates. According to the article published by K. Jowano itsch in "Monatshef te" Nr. 6, pp. 467-476 (1885), the tartaric acid in the glycerin is dehydrated or decarboxylated to form a pyruvic acid glycid, which subsequently reacts with lime in an aqueous solution to form calcium pyruvate. As stated in the above according to the examples contained in this publication, this process does not result in the formation of calcium pyruvates, but that of polymeric pyruvic acid derivatives. According to French Patent No. 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 or unstable calcium pyruvates are obtained, which contain more than 2.5 moles of water of crystallization and occur in the form of ions of 2,2-dihydroxypropionate. to These reaction products as a rule contain little calcium pyruvate and comparatively large amounts of side products, since pyruvic acid or pyruvate ion reacts by addition of aldol or condensation of aldol to form acrylic or cyclic dimers and polymers of pyruvic acid. With respect to the acyclic compounds, a particular mention is made herein of pa ra -pi ru vi co acid (4-hydr oxy-4-methyl-1-oxoglyc acid) and its salts, and the products of high addition of aldol. Oxalic acid and methyl ester can also be formed as byproducts.

By means of the 1 ac t ion, ketalization and other reactions, the acyclic pyruvic acid polymers can, in turn, form cyclic compounds such as 5-lactone 2-hydrox ox i-2-methyl ester. 1-4 -oxoglutaric acid and tri-carboxylic acid, tri-phasic, isophthalic and pyranic acid derivatives. These side products can be formed in a similar way when the calcium pyruvates containing more than 2.5 moles of water of crystallization are stored. The calcium pyruvates known from the prior art in this way are not suitable for therapeutic uses (trapping free radicals, cellular protection, obesity, etc.) or as a food supplement, due to the fact that during the production and storage of these pyruvates secondary products and products of the decomposition of pyruvic acid and its salts are formed which can be physiologically incompatible or even toxic . The object of this invention then is to develop a method for producing calcium pyruvates which does not have the disadvantages of the methods known from the prior art, and with which highly pure calcium pyruvates with a long shelf life can be obtained, which are largely free of secondary products that may have a logical effect. This object was established according to the invention by reacting calcium salts of organic acids of acidic keto or hydroxy organic compounds with pyruvic acid at a temperature in the range of -20 to + 120 ° C, optionally in the presence of a diluent or solvent Surprisingly, it was found that calcium pyruvates can be obtained in this manner widely anhydrides with high purity. Calcium pyruvates produced in this way are also thermostable and have a very long shelf life. This is surprising, because pyruvic acid is a relatively unstable compound, and the calcium pyruvates hitherto known decompose in a short period of time to form dimeric and polymeric derivatives of pyruvic acid. According to the method of this invention, as indicated above, the calcium salts of organic acids or acidic keto or hydrioorganic compounds were reacted with pyruvic acid at a temperature in the range of -20 to + 120 ° C, preferably from 10 to 60 ° C. Suitable organic acids include, for example, aliphatic monocarboxylic acids which may also bear substituents such as OH-, CO-, CN-, Cl- or Br- groups and which may also be mono- or polyunsaturated. Examples of such monocarboxylic acids are formic acid, acetic acid, propionic acid, butyric acid and lactic acid. For the method of the invention, aliphatic di and tricarboxylic acids can also be used; these can also be mono or polyunsaturated and can also carry their ingredients as OH groups. Examples of such acids are citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, and malic acid. Instead of organic acids, organic keto or hydroxy organic compounds such as ascorbic acid can also be used. These calcium salts can be used in the anhydrous form, as hydrates or as wet products. Particular preference is given to physiologically compatible compounds which are approved by the law of 1 to 1.

According to the method of the invention, the pyruvic acid can also be used in the anhydrous form, in aqueous solution or dissolved or suspended in an organic solvent or diluent. The scope of the invention also provides the production of pyruvic acid in situ, ie, as an intermediate, for example, by reacting an alkali metal pyruvate such as potassium or sodium pyruvate with an organic acid such as hydrochloric acid. or sulfuric at a temperature in the range of -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, cyclohexane 1), ethers (diethyl ether, tetrahydrofuran, 1,4-dioxane), ketones ( acetone, methyl ethyl ketone, cyclohexanone), esters (methyl acetate, ethyl acetate, ethyl formate), organic acids (formic, acetic, propionic, lactic and pyruvic acids), nitriles (acetonitrile) as well as aliphatics (pentane, hexane, cyclohexane) and aromatic hydrocarbons (toluene). However, it is also very possible to react the organic calcium salts with pyruvic acid in the absence of solvents or diluents. The ratio of organic calcium salt to pyruvic acid can vary within wide limits; suitable molar proportions may vary, for example, from 10: 1 to 1:20, preferably from 5: 1 to 1:10. However, it has proven to be particularly advantageous if the organic calcium salts and the pyruvic acid are reacted in proportions which are typically approximately equal, for example, in a molar ratio of 2: 1 to 1: 4. The reaction of the invention can be carried out without problems, and it is conducted using common techniques and customary apparatuses such as mixers, mixers, paddle dryers and agitator vessels. In this way, a high yield (> 95%) of a high purity (> 97%) of calcium pyruvates is obtained without the need for purification steps that take time. It is particularly important that the method of the invention allows the preparation of novel calcium pyruvates which are not only very pure but also have a very long shelf life and, furthermore, are widely anhydrous and have the following structural formula : As established by means of an IR spectroscopic examination, the calcium pyruvates produced according to the invention which contain 2.5 moles or less of water of crystallization, are obtained mainly as the 2-oxo-p rop ionone ion. By virtue of their high level of purity and very good storage properties, the calcium pyruvates produced according to the method of the invention are excellently suitable as components of physiologically compatible compositions, for example for applications in the field of medicine and as Food supplements . The calcium pyruvates produced according to the invention in this way can be used together with at least one other physiologically compatible substance selected, for example from the group comprising pharmaceutical active ingredients, pharmaceutical carriers and auxiliaries, vitamins, mineral substances, carbohydrates and other food supplements for making physiologically compatible compositions. These calcium pyruvates are particularly suitable in the field of sports to improve stamina and vigor, in the health field to reduce weight and body fat, as a protective substance for tissues and body cells, especially neuronal, nephrotic, hepatic tissue , peritoneal and cardiovascular) and as the substance which inhibits the formation of free radicals and which eliminates free radicals in tissues and body cells (including synovial tissue), and also to treat obesity and weight problems and as a dietary supplement. The following examples serve to explain the invention in more detail.

Example 1 81 g (0.46 mole) of calcium acetate monohydrate were added over a period of 1 hour at 20 ° C to a solution of 88 g (1 mole) of pure pyruvic acid (99%) in 400 ml of ethyl acetate. ethyl ether and stirred for 18 hours. The formed calcium pyruvate is subsequently filtered by vacuum and washed with 2 x 250 ml of ethyl acetate. The production of calcium pyruvate monohydrate is 102 g (95% of theoretical production) (C3H303) 2Ca x 1H20, calculated: C 31.04%, H3.47%, Ca 17.26% found: C 31.19%, H 3.58% , Ca 17.20%; PF > 300 ° C; IR (KBr) [1 / cm]: 634, 742, 832, 1185, 1354, 1402, 1643, 1713, 3195, 3480; 1 R-NMR (D20, 300 MHz): d = 2.36 (s, 3 H, CH 3 -CO), 1.49 (s, 3 H, CH 3 -C (OH) 2); content of CLAP (calcium pyruvate): 92.1% = 99.8% calcium pyruvate monohydrate.

T h e 2 9.5 g of water were added to a solution of 45.5 g (0.5 mole) of 98.7% pyruvic acid in 200 ml of glacial acetic acid for a period of one hour at 40 ° C, 41.8 g were introduced ( 0.25 moles) of calcium acetate is emihydrated. The mixture was stirred at 40 ° C for an additional 3 hours, then cooled to 15 ° C and stirred for another hour. The calcium pyruvate was then filtered by vacuum, washed with 2 x 100 ml of ethyl acetate and dried at 50 ° C and 15 mbar. The production of calcium pyruvate monohydrate is 55 g (95% of the theoretical production).

Example 3 At a temperature of 15 to 20 ° C and for a period of 45 minutes, 64.3 g (0.49 mole) of 70% sulfuric acid in the drop form was added to a suspension of 110 g (1 mole) of pyruvate. sodium in 200 ml of ethyl acetate. After 3 hours, the precipitated sodium sulfate was filtered under vacuum and washed with 2 x 40 ml of ethyl acetate. 250 g of concentrated acetic acid were added to the filtrate, and the mixture was heated to 35 ° C. Within a period of 30 minutes, 80.2 g (0.48 moles) of calcium acetate were introduced. The low viscosity suspension was stirred for an additional 3 hours, after which the calcium pyruvate was filtered under vacuum and washed with 2 x 100 ml of ethyl acetate. The product was dried at a constant weight at 50 ° C in a vacuum drying chamber. The production of calcium pyruvate monohydrate was 107 g (96% of the theoretical yield).

In a laboratory mixer, 88 g (1 mole) of pyruvic acid was added at 20 ° C and for a period of 30 minutes at 84 g (0.5 mole) of calcium acetate was added, and Knead for 2 hours. The calcium pyruvate, moistened with acetic acid, was then dried at 50 ° C and 12 mm Hg in a vacuum drying chamber. The production of calcium pyruvate hemihydrate is almost quantitative (> 99% of the theoretical production).

Example 5 20 g of water were added to a solution of 45.5 g (0.5 mol) of 98.7% pyruvic acid in 200 ml of glacial acetic acid and, during a period of one hour at 40 ° C, 32.5 g (0.25 g) were introduced. moles) of calcium formate. The mixture was stirred at this temperature for 3 hours, then cooled to 15 ° C and stirred for another hour. The calcium pyruvate was then vacuum filtered, washed with 2 x 100 ml ethyl acetate and dried at 50 C and 15 mbar. The production of calcium pyruvate trihydrate was 65 g (97% of the theoretical yield).

(C3H3? 3) 2Ca x 3H20, calculated: C 26.87%, H 4.51%, Ca 14.94%; found: C 26.77%, H 4.53%, Ca 14.70%; PF > 300 ° C; IR (KBr) [1 / c]: 668, 789, 862, 934, 965, 1142, 1182, 1408, 1610, 3430; 'H-NMR, 300 MHz): 5 = 2.36 (s, 3H, CH3-CO), 1.49 (s, 3H, CH3-C (OH) 2); content of CLAP (calcium pyruvate): 79.4% = 99.4% calcium pyruvate trihydrate.

Example 6 (Comparison) The method described in "Monatshefte" 6, 467-476 (1885) (K. Jo -ano itsch) was used. A mixture of 40 g of glycerin and 32 g of tartaric acid was heated at 140 ° C until that there was no more steam escape. Then the mixture was heated to 260 ° C, being subjected to fractional distillation under gas formation. The first fraction was a low viscosity emulsion, from which 0.2 g of a crystalline solid were separated. This solid proved to be a pyruvic glycide from the NMR, IR and GC-MS analyzes. It was completely dissolved in 5 ml of water, and then 80 g of calcium carbonate was added, the mixture was heated and boiled for 30 minutes. Once the excess calcium carbonate was removed, the aqueous solution was analyzed by CLAP chromatography. However, no calcium pyruvate could be detected.

Claims (16)

1. Method for producing calcium pyruvates, wherein the calcium salts of organic acids or acidic keto or hydroxy organic compounds are reacted with pyruvic acid at a temperature in the range of -20 to + 120 ° C, and pyruvates are obtained of calcium formed in this way. flp.0

2. The method of claim 1, wherein the aliphatic monocarboxylic acid serves as the organic acid.

3. The method of claim 1, wherein an aliphatic di or t r i c a rb ox iic acid serves as an organic acid.

4. The method of claim 1, wherein the ascorbic acid serves as a keto compound or 20 hydroxy organic acetic.

5. Method according to one of claims 1 to 4, wherein the pyruvic acid is produced in situ.

The method of claim 5, wherein the pyruvic acid is formed as an intermediate by reacting an alkali metal pyruvate with an inorganic acid such as sulfuric or hydrochloric acid.

7. Method according to one of the rei indications 1 to 6, wherein the reaction is carried out at a temperature in the range of 10 to 60 ° C.

8. Method according to one of claims 1 to 7, wherein the reaction is carried out in the presence of a solvent or diluent.

9. The method of claim 8, wherein an organic solvent and / or water is used as a solvent or diluent.

10. The method of claim 9, wherein the organic solvent is selected from the group comprising alcohols, ethers, ketones, esters, organic acids, nitriles, aliphatic and aromatic hydrocarbons and mixtures thereof.

11. Method according to one of the rei indications 1 to 9, wherein the pyruvic acid and the organic calcium salts are reacted in a molar ratio of 2: 1 to 1: 4.

12. Method according to one of the rei indications 1 to 11, wherein the obtained calcium pyruvates are used to make a physiologically compatible composition.

13 P rotective coughs of the f or rmu the general of 2.5)

14. The physiologically compatible compositions which contain calcium pivurates according to claim 13, together with at least one other physiologically compatible substance selected from the group comprising pharmaceutically active ingredients, pharmaceutical carriers and auxiliaries, vitamins, mineral substances, carbohydrates and other food supplements. .

15. Use of the calcium pyruvates of claim 13 to produce an agent to improve stamina and vigor in the sports field, to reduce weight and body fat, as a protective substance for body tissues and cells and as a substance which inhibits formation of free radicals and which eliminates free radicals in tissues and body cells in the field of health care and also to treat obesity and weight problems and as a dietary supplement.

16. Method according to one of claims 1 to 12, wherein the calcium pyruvates - obtained are used to produce an agent to improve stamina and vigor in the field of sport, to reduce weight and body fat, as a protective substance for tissues and body cells and as a substance which inhibits the formation of free radicals and which eliminates the free radicals in tissues and body cells in the health area of both obesity treatments and weight problems and as supplementation methods. imen t icio.