CS256206B1 - A process for preparing a zinc aspartic acid complex - Google Patents

Abstract

The essence of the solution is a method of preparing a zinc complex of aspartic acid of formula I CH.-COO-. 1 2 „.-n2° CH - NH5- - - · 1 2 - ' -?-'Ζης-- H2O (I), co - 0 - ' '~-h2o which is based on the reaction of aspartic acid with an equimolar amount of an inorganic base from the group including hydroxides and bicarbonates of ammonium and alkali metals, the resulting aqueous solution of hydrogenaspartate is allowed to react with an equimolar amount of an inorganic zinc salt dissolved in water at a temperature of 40 to 100 °C, the pH of the reaction mixture is then adjusted to a value of 6.0 to 7.5, the obtained solution is cooled to a temperature of 0 to 20 °C and the precipitated product is dried after washing with water at a temperature of 40 to 100 °C. The complex compound of formula I can be used alone or in the form of a mixture with an appropriate representation of other components as a geriatric in healthcare.

Description

The invention relates to a process for the preparation of a therapeutically useful zinc aspartic acid complex of formula I ch ₂ -coo, h ₂ o

CH-NH, -'r-Zn'-H.O (I)

I V - '-, ²

CO - O 'H ₂ O

It is known that complex aspartic acid compounds with biogenic metals are therapeutically advantageous forms of medicinal products because of their physiological safety and ease of absorption. For example, magnesium-potassium aspartic acid is a proven cardiotonic and is produced under the name Cardilan. Aspartic acid itself is a part of polycomponent infusion solutions (Nutramines), which are intended for nutrition of patients when food cannot be administered orally or for the treatment of liver insufficiency.

The preparation of zinc aspartic acid complexes has not been explicitly described in the literature. Although the complex of formula I is known and in the literature (Doyne, T.H. et al .: Acta Cryst. 1, 652 (1954), Doyne, T.H. et al .: Acta Cryst. 10, 438 (1957), Doyne,

TH: Dis. Abstr. 18, 52 (1958), Kryger, L., Rasmussen, S., Acta Chem. Scand. 27, 2674 (1973)), its crystal structure has been solved and no reference is made to the method for its preparation. An analogous method to the synthesis of the isostructured compounds NiAsp.3H ₂ O and CoAsp.3H ₂ 0 (Lifschitz, I., Sohouteden, FLM) was probably used in the synthesis:

Speech. Trav. CHim. 58, 411 (1939)), which is based on the reaction of aspartic acid with nickel carbonate, respectively. and the product is isolated after concentration of the aqueous solution to dryness. The preparation of complex compounds of aspartic acid with monovalent and divalent metals (Tanner, H., Scherberich. P .: Ger. Offen 2,752,287) is too general and does not lead to defined products in the case of zinc.

SUMMARY OF THE INVENTION The present invention is directed to a process for the preparation of a zinc aspartic acid complex of formula I, wherein the aspartic acid is reacted in an aqueous medium with an equimolar amount of an inorganic base selected from the group consisting of alkali metal and ammonium hydroxides and bicarbonates. is reacted with an equimolar amount of inorganic zinc salt dissolved in water at 40 to 100 ° C, the pH of the reaction mixture is adjusted to 6.0 to 7.5 by adding one of the above inorganic bases, the solution obtained is cooled to 0 to 20 ° C and the precipitated product is dried at 40 to 100 ° C after washing with water.

The process according to the invention is carried out by stirring 1 mol of aspartic acid in distilled water, adding 1 mol of inorganic base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium bicarbonate, potassium bicarbonate or ammonium bicarbonate, to the suspension. Stir until the solution is clear. The resulting aqueous alkali metal or ammonium hydrogen aspartate solution is reacted with 1 mole of zinc salt, such as zinc sulfate, zinc nitrate, or preferably zinc chloride, wherein the zinc salt is dissolved in distilled water. The reaction is carried out at a temperature of 40 to 100 ° C, preferably at a temperature of 70 to 80 ° C, then the pH of the solution is adjusted. by adding any of the above inorganic bases to a value of 6.0 to 7.5, preferably to a value of 6.0 to 6.3, and the solution is filtered. The filtrate is cooled to 0 to 20 ° C and the solution is left to crystallize for 1 to 4 hours. The precipitated product is washed with distilled water and dried at 40-100 ° C to constant weight.

The resulting zinc aspartic acid complex of formula I is very pure and has a defined composition. In addition, it is very stable in the dry state and can therefore be stored and processed to the desired dosage form without decomposition. The zinc aspartic complex prepared according to the invention can be used either alone or in the form of a mixture with a suitable representation of the other components as active geriatrics. Its application is possible in various dosage forms, such as tablets, coated tablets, dragees, granules, syrups, suspensions or solutions, both in human and veterinary practice.

Further, the invention is described by way of examples, which illustrate some of the possibilities for preparing the compound of formula I in more detail, without limiting the scope of the invention in any way.

Example 1

40.0 g (1 mol) of sodium hydroxide are dissolved in 500 ml of distilled water and 133.1 g (1 mol) of L-aspartic acid are added. The mixture is stirred until all the aspartic acid has dissolved, i.e. about 15 minutes. To the sodium hydrogen aspartate solution thus prepared is added a solution formed by dissolving 136.3 g (1 mol) of zinc chloride (anhydrous) in 250 ml of distilled water. The resulting mixture is stirred vigorously, heated to 75-80 ° C, with stirring, at which temperature a solution of 40.0 g (1 mol) of sodium hydroxide in 250 ml of distilled water is added in portions until the final pH of solution 6. 0 to 6.3 (almost the entire volume of sodium hydroxide solution is used). The solution thus obtained is filtered while still warm and allowed to crystallize for 2 hours with stirring and cooling to 10 DEG C. The precipitated product is then separated by filtration or centrifugation, washed with 2 x 250 ml of distilled water, 2 x 250 ml of anhydrous ethyl alcohol and vacuum. Dry at 80 ° C to constant weight.

188 g (75.0% of theory) of a white crystalline substance of formula I which is poorly soluble in cold water were obtained. The total formula is C ^H ^^O OWZn and the relative molecular weight is 250.52 g / mol. The structure of the isolated complex of formula I was confirmed by elemental analysis and thermogravimetry.

Elementary analysis: calculated: found: % C = % C = 19,18, 20.11 % H = 4.43 % H = 4.37 % N = 5.59 % N = 5.72 Determination content zinc (potentiometrically and polarographically)

calculated:% Zn = 26.09 found:% Zn = 27.04 (potentiometrically)% Zn = 26.30 (polarographically)

Water content (thermogravimetric): calculated:% H ^ O - 21.56 found:% I ^ O = 22.34

Results of thermogravimetric analysis:

The DTA curve shows that at about 145 ° C, all three water molecules are cleaved with simultaneous decomposition of the complex (aspartic acid decarboxylates). This implies that all three water molecules are part of a coordinating polyhedra. These results, together with elementary analysis, unambiguously confirm the proposed structure.

Example 2

The procedure is the same as in Example 1, except that an appropriate amount of sodium bicarbonate was used as the inorganic base both for the preparation of the mono2 + sodium salt and for the alkalization of the final solution. Zn sulphate was used as the Zn source and the product obtained was washed with water and anhydrous methanol before drying. After drying, 182 g (72.6% of theory) of the complex of formula I were obtained. The structure of the obtained compound was confirmed by elemental analysis and thermogravimetry, similar to Example 1.

Example 3

The procedure was the same as in Example 1 except that an appropriate amount of potassium hydroxide was used as the inorganic base both for the preparation of the monopotassium 2+ salt and for the alkalization of the final solution. An appropriate amount of zinc nitrate was used as the Zn source. The isolation proceeded as in Example 1. After drying, 176 g (70.3% of theory) of the complex of formula I were obtained. The structure of the obtained compound was confirmed by elemental analysis and thermogravimetry, similar to Example 1.

Example 4

The procedure was the same as in Example 1, except that an adequate amount of ammonium hydroxide was used as the inorganic base both for the preparation of the monoammonium salt and for alkalization of the final solution to pH = 6.0 to 6.3. Again, the procedure was the same as in Example 1. 185 g (73.8% of theory) of the complex of formula I were obtained. The structure of the obtained compound was confirmed by elemental analysis and thermogravimetry.

Example 5

The procedure was the same as in Example 1, except that an appropriate amount of ammonium bicarbonate was used as the inorganic base both for the preparation of the monoammonium salt and for the alkalization of the final solution to a pH of 6.0 to 6.3. The procedure was again identical to that in Example 1. After drying, 181 g (72.2% of theory) of the complex of the formula were obtained.

I. The structure of the isolated substance was confirmed by elemental analysis and thermogravimetry, as in Example 1.

Claims (4)

A process for the preparation of a zinc aspartic acid complex of formula I ch ₂ -coo. 'H ₂ o CH - NH ₂ - '- Zn -' H ₂ O (I), CO-O- ^H 2 ° characterized in that the aspartic acid is reacted in an aqueous medium with an equimolar amount of an inorganic base selected from the group consisting of ammonium and alkali metal hydroxides and bicarbonates, and the resulting aqueous hydrogenasparagan solution is reacted with an equimolar amount in water dissolved inorganic zinc salt at 40 to 100 ° C, the pH of the reaction mixture is adjusted to 6.0 to 7.5 by addition of one of the above inorganic bases, the solution obtained is cooled to 0 to 20 ° C and the precipitated product is after washing with water, it is dried at 40 to 100 ° C. 2. The process according to claim 1, wherein the inorganic zinc salt is zinc sulfate, zinc nitrate or zinc chloride. 3. The process according to claim 1, wherein the reaction is carried out at a temperature of 70 to 80 ° C. 4. Process according to claim 1, characterized in that the isolation of the product takes place preferably after the pH of the reaction solution has been adjusted to a value of 6.0 to 6.3.