Method of obtaining complex acidic salts of divalent metals and dicarboxylic acids

Abstract

A method of obtaining a complex acidic salt of a divalent metal and a dicarboxylic acid includes heating water in a reactor; adding a dicarboxylic acid to the heated water; stirring the water to dissolve the dicarboxylic acid in the heated water to produce a solution or a suspension of the dicarboxylic acid in the heated water; adding MeO to the solution or the suspension, where Me is a divalent metal; continuing the stirring of the solution or suspension until formation of the complex acidic salt Me(AcH).sub.2.nH.sub.2O begins, where Ac is an anion of the dicarboxylic acid, and n=0-8; cooling the complex acidic salt to below a temperature of crystallization; sedimenting the complex acidic salt; filtering the complex acidic salt to remove water from the complex acidic salt; and drying the complex acidic salt.

Claims

1. A method of obtaining a complex acidic salt of a divalent metal and a dicarboxylic acid, the method comprising: heating water in a reactor; adding a dicarboxylic acid to the heated water to produce a suspension of the dicarboxylic acid in the water; stirring the water to dissolve the dicarboxylic acid in the heated water so as to convert the suspension into a solution of the dicarboxylic acid in the heated water; during the stirring, and while the suspension is being converted to the solution, adding MeO to the reactor, where Me is a divalent metal, and wherein a molar ratio of the dicarboxylic acid and the MeO in the heated water is 2.005:1-2.1:1; continuing the stirring until formation of the complex acidic salt Me(AcH).sub.2.nH.sub.2O begins, where Ac is an anion of the dicarboxylic acid, and 0<=n<=8; cooling the complex acidic salt to below a temperature of crystallization of the complex acidic salt; sedimenting the complex acidic salt; filtering the complex acidic salt to remove water from the complex acidic salt; and drying the complex acidic salt.

2. The method of claim 1, wherein the divalent metal is any of potassium, magnesium and zinc.

3. The method of claim 1, wherein the dicarboxylic acid is any of L-aspartic acid, L,D-aspartic acid, fumaric acid and amber acid.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) Reference will now be made in detail to the preferred embodiments of the present invention.

(2) The objective is a process that results in a more effective method of synthesis of complex salts with a general formula: Me(AcH).sub.2.nH.sub.2O, (I), where Me—divalent cation, Ac—anion of dicarboxylic acid, H—hydrogen, n≧0. There is a need for synthesis of complexes with defined composition, because complexes with the same composition but with different Me:Ac ratios have different physical, chemical, and biological properties, and complex salts that have the same composition but different degrees of hydration have different pharmacokinetics and different abilities to interact with other components of drugs and foods.

(3) The presented problem is solved by conducting the synthesis in such a way that constant, equal to the initial, ratios between all components of the reaction are maintained in the reaction volume.

(4) To do this, an oxide of divalent metal dissolved in water immediately before the reaction is used as a “basic” agent. The reaction is conducted with stirring, in a way that provides mixing of the entire volume in the reactor; control of the flow speed provides turbulent movement of the fluid.

(5) In practice, to obtain a salt with the ratio Me:Ac=1:2, components are added to the reactor not with the stoichiometric ratio 1:2, but with molar ratio MeO:AcH.sub.2=1:2.005-1:2.10. Decrease of the ratio below 2.01 leads to the formation of neutral salts; increase in the ratio above 2.10 leads to the formation of salts that will have more than 2 dicarboxylic acid anions in their structure.

(6) Oxides of zinc, magnesium, and calcium are most often used as metal oxide reagents; amber, fumaric, L-aspartic, L,D-aspartic acids—as dicarboxylic acid reagents.

(7) The proposed method allows producing complex acidic salts of divalent metals and dicarboxylic acids with given composition with the main product making up at least 95% of the mass. The product can be either completely dehydrated during drying or have a predetermined amount of water.

(8) Salts obtained by the method proposed here do not have biological activities on their own; their combination makes them potentially very useful for activation and regulation of a number of main metabolic processes in animals. Based on the proposed invention, when combined with other compounds, the biological activity of complex salts becomes extremely high and not replaceable by other known substances with identified biological activity. There is a pronounced synergetic effect, which cannot be obtained by other means.

(9) Key to the symbols provided in the examples below:

(10) SucH.sub.2 HOOC—CH.sub.2—CH.sub.2—COOH—amber acid

(11) SucH HOOC—CH.sub.2—CH.sub.2—COO.sup.−—amber acid anion

(12) FumH.sub.2 HOOC—CH═CH—COOH—fumaric acid

(13) FumH HOOC—CH═CH—COO.sup.−—fumaric acid anion

(14) AspH.sub.2 HOOC—CH(NH.sub.2)—CH.sub.2—COOH—aspartic acid

(15) AspH HOOC—CH(NH.sub.2)—CH.sub.2—COO.sup.−—aspartic acid anion

Example 1. Comparative

(16) 118 g of amber acid and 25 g of calcium carbonate are dissolved in 600 ml of water at room temperature (˜25° C.) (salt concentration—17.6% mass). The solution is poured over a paper filter and is incubated at room temperature for 24 hours. The solution is then slowly (for 20 min) heated to 100° C. and is evaporated at this temperature for 6 hours.

(17) The resulting precipitated is dried to a constant mass. Yield (127.5 g)—100% of the theoretical.

(18) Ca content (complexometric titration) corresponds to the ratio Ca:Suc=1:4; this is because the initial components are loaded in that same ratio, and all of the water is removed from the reaction mass. However, based on the NMR analysis (labeled carbon and hydrogen), the result is the mixture of complex calcium succinate salts, where about 84% is calcium tetrasuccinate and the remaining 16%—a mixture of less acidic calcium succinates (CaSuc, CaSuc.sub.2, CaSuc.sub.3) and complex calcium salts with the ratio Ca:Suc=1:5 and higher.

Example 2. Synthesis of Acidic Magnesium Succinate

(19)
2SucH.sub.2+MgO+3H.sub.2O Mg(SucH).sub.2.4H.sub.2O

(20) 3.7 L of water is loaded in the reactor and heated to 80-85° C. Amber acid (5.4 kg, 5% stoichiometric excess) is suspended in the water while stirring. At this temperature, 3.2-3.4 kg of amber acid in the form of a saturated aqueous solution of (concentration 41.2-44.5% mass) can be obtained.

(21) After a 30-40 min incubation to stabilize the mixture, 925 g of magnesium oxide (95% purity) is added in portions with constant stirring. The stirring is continued at 80-85° C. until the solution of the complex salt is obtained—acidic magnesium succinate (concentration ˜71% mass). After that the reaction mass is slowly (less than 0.5° C. per minute) cooled to ˜75° C.—the temperature at which salt crystallization from the saturated solution begins, as well as dosage of the initial components.

(22) Drying at 60-80° C. in a tray dryer allows obtaining dehydrated salts; drying under a warm air flow (30-40° C.) produces a tetrahydrate as the final product.

(23) When drying with warm air (less then 50° C.), the resulting salt is tetra-aqueous crystal-hydrate with 98.8% mass of the main ingredient (complexometric titration). Magnesium content is 7.27% mass (atomic absorption spectrometry).

Example 3. Synthesis of Acidic Calcium Succinate

(24) $2{\mathrm{SucH}}_2+\mathrm{CaO}\underset{-2H_{2}O}{.fwdarw.}{\mathrm{Ca}\left(\mathrm{SucH}\right)}_2$

(25) 7.7 L of water is heated to 90-95° C. While stirring, 2.04 kg of amber acid (3% stoichiometric excess) is dissolved in the water and 577 g of calcium oxide (97% purity) is added slowly to the reaction zone, each portion is added after the previous one has dissolved. The resulting salt solution (with the concentration about 22% mass) is cooled to ˜80° C., at which point crystallization of the precipitate begins. After that, the process is conducted as in example 2.

(26) This allows to obtain both the dehydrated salt (drying at 105-110° C.) and the monohydrate (drying with warm air or vacuum at 30-40° C. and 15-20 mm Hg). The content of the main compound—acidic calcium succinate—at least 97%, content of the neutral salt (CaSuc.H.sub.2O)—no more than 3% mass.

Example 4. Synthesis of Acidic Zinc Fumarate

(27)
2FumH.sub.2+ZnOZn(FumH).sub.20.5H.sub.2O+0.5H.sub.2O

(28) 299.8 g of fumaric acid (1% stoichiometric excess) is dissolved in 9.62 L of water and heated to ˜95° C. with stirring. 108 g of zinc oxide is slowly added to the solution (concentration about 3% mass) of fumaric acid, constantly stirring until the solution is formed. The solution is then cooled slowly (0.8-1.0° C.) until crystallization begins (˜85° C.). After that, the synthesis of the salt is conducted at 80° C., forming precipitate is separated by filter; the concentrations of fumarate anion (or cation of zinc) are controlled by maintaining their constant amounts in the reaction volume (see Example 2).

(29) After drying with vacuum (45-50° C., 15-20 mm Hg), salt Zn(FumH).sub.20.5H.sub.2O is obtained with 98.5% purity. Zn content—21.16% (X-ray fluorescence analysis).

Example 5. Synthesis of Acidic Magnesium Aspartate

(30)
2AspH.sub.2+MgO+3H.sub.2OMg(AspH).sub.2.4H.sub.2O

(31) 8.6 L of water is heated to 90-95° C. and 1.3 kg (˜0.5% stoichiometric excess) of aspartic acid is added, stirred and a suspension (˜750 g) of aspartic acid in its saturated solution (concentration ˜6%) is obtained. 198.5 g of magnesium oxide (98.5% purity) is added in portions to the above solution with constant stirring. After mixing, a solution of magnesium aspartate (concentration ˜17% mass) is obtained and is cooled until crystallization begins (65-70° C.). After that—see Example 2.

(32) After drying (80° C., tray dryer) magnesium aspartate is obtained in the form of 4× water crystal-hydrate of 99.5% mass purity.

Example 6. Synthesis of Acidic Calcium Succinate Dihydrate

(33)
2SucH.sub.2+CaO+H.sub.2OCa(SucH).sub.2.2H.sub.2O

(34) 640 L of water is loaded into a reactor and is heated to 70-75° C. 480 kg of 100% amber acid (from molar ratio AA:CaO=2.1:1) is added in portions while the reaction continues to heat to 80-85° C., until the acid is completely dissolved.

(35) Water suspension of calcium hydroxide (which is obtained by slaking—108.5 kg of calcium oxide in 385 L of water in a working, preferably enameled container) is added in a small stream, slowly and evenly, while stirring.

(36) The reaction mass is incubated in the reactor at 85-90° C., with stirring, for 1 day until the reaction is completed.

(37) When the incubation is completed, the heat is turned off and, with a constant stirring, the reaction mass is cooled in two steps: first to ˜70° C. (self-cooling), then to 16-18° C. by pouring cold water in the jacket of the reactor. Acidic calcium succinate crystallizes in the form of 2× water crystal-hydrate.

(38) After crystallization is complete, the cooled suspension is filtered in several steps, in portions of about 150 L. All of the obtained wet precipitate is additionally separated from the solution by centrifugation until remaining water is ˜5-7% mass. The precipitate is then dried.

(39) The drying of the wet precipitate salt is conducted in the drying oven at 40-50° C.—to obtain acidic calcium succinate in the form of 2× water crystal-hydrate.

(40) The total amount of dry product (acidic calcium succinate 2× hydrate) obtained from one round of synthesis is 485-506 kg.

Example 7. Zinc Fumarate, Acidic Monohydrate

(41)
2FumH.sub.2+ZnOZn(FumH).sub.2.H.sub.2O

(42) 13 L of water is loaded in the reactor and, with constant heating and stirring, 11.9 kg of fumaric acid is suspended in it. The suspension is heated to ˜60° C., and zinc oxide is added in portions (suspension prepared in a separate container immediately before this step, 4.17 kg of zinc oxide and 10 L of water). The reaction mass is then incubated for 2 hours with stirring (with partial evaporation), while continuously heated to 80-90° C.

(43) After the incubation is completed, the heat is turned off and the cooling of the reaction mass to ˜60° C. (self-cooling) is done with stirring. The reaction mass is then loaded into a crystallizer and cooled to 16-18° C.

(44) The formed suspension is filtered in portions, the precipitate is wringed out and 18-20 kg of precipitate with ˜30% moisture mass is obtained. The wet precipitate is dried in the warm air stream (40-50° C.). 14-15 kg of dry product is obtained; the main component makes up 99.2% (zinc content—20.86%).

Example 8. Testing the Incorporation of the Dicarboxylic Acid Anions (Components of the Produced Compounds) in Metabolic Processes

(45) For these studies, compounds were synthesized as described in examples 2-7, but using .sup.13C-labeled amber, aspartic and fumaric acids. The signal incorporation in metabolism was determined by exhalation of the labeled .sup.13C atom in the form of .sup.13CO.sub.2. The experiment was conducted as follows: aqueous solutions, in the amounts equivalent to 1 mg of the acids anions they contained, were administered to rats (groups of 8 individuals, each rat weighing 225-250 g) with a pipette: amber acid, sodium fumarate (fumaric acid is almost insoluble in water), aspartic acids, Ca(SucH).sub.2, Mg(SucH)2.4H.sub.2O, Mg(AspH).sub.2.4H.sub.2O, Zn(FumH).sub.2.0.5H.sub.2O, Zn(FumH).sub.2.H.sub.2O. The animals were then quickly placed in a hermetically sealed chamber. The air from the chamber was sampled in the same amount as it was pumped in the chamber. The air collected 12 hours after solutions have been administered was analyzed for 13C content in CO.sub.2; the baseline concentration was disregarded since it did not exceed 0.1%. After that, the mass % of 13C administer was calculated in the exhaled air. The following results were obtained: amber acid—99.4%, sodium fumarate—97.8%, aspartic acid—59.4%, Ca(SucH).sub.2—49.7%, Mg(SucH).sub.2.4H.sub.2O—47.7%, Mg(AspH).sub.2.4H.sub.2O—47.4%, Zn(FumH).sub.2.0.5H.sub.2O—43.5%, Zn(FumH).sub.2.H.sub.2O—41.4%. As the results clearly show, anions of all tested compounds are actively included in the cellular metabolic processes.

(46) Having thus described a preferred embodiment, it should be apparent to those skilled in the art that certain advantages of the described method have been achieved.

(47) It should also be appreciated that various modifications, adaptations, and alternative embodiments thereof may be made within the scope and spirit of the present invention. The invention is further defined by the following claims.

REFERENCES

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