Recovery of Methionylmethionine from an Aqueous Alkaline Metal Ion-Containing Medium

Abstract

The present invention relates to the recovery of methionylmethionine from an aqueous alkaline ion-containing medium by the formation of an intermediate of bis(methionyl)-diketopiperazine.

Description

Technical Field

[0001] The present invention relates to the recovery of methionylmethionine from an aqueous alkali metal ion-containing medium by formation of an intermediate of bis(methionyl)-diketopiperazine.

[0002] Methionine is an essential amino acid, i.e., an amino acid that must be supplied in the process of livestock production to promote animal growth. The dipeptide DL-methionyl-DL-methionine (hereinafter also referred to as "methionylmethionine" or "MetMet"; sold by Evonik Operations of Germany as AQUAVI® MetMet) contains two chemically linked methionine units and has the advantage of showing a sustained-release effect and / or a delayed-release effect due to its lower water solubility compared to methionine itself. This is particularly suitable as a feed component for aquaculture applications where elution of monomeric amino acids is usually a problem, as documented, for example, in WO 2010 / 043558. However, the sustained-release effect and / or the delayed-release effect is also beneficial in feeding classical livestock such as poultry and pigs.

[0003] MetMet can be produced from methionine hydantoin and an alkali base supplied from the methionine process to obtain the intermediate 2,6-bis(methionyl)-1,4-diketopiperazine (hereinafter also referred to as "DLLD / DDLL-Met-DKP" or "Met-DKP"). After purification, this Met-DKP can be hydrolyzed under basic conditions and then neutralized with sulfuric acid to obtain the desired MetMet according to formula (I) (see also WO 2010043558).

Chemical formula

[0004] However, in the chemical production of methionine, a significant amount of by-products containing MetMet are produced in large quantities. Therefore, the question has arisen as to whether the MetMet contained in such by-products can be utilized to enhance the overall efficiency of the methionine production process.

[0005] Methionine is chemically produced, for example, via the Bucherer-Bergs reaction, a variant of the Strecker synthesis. Here, the starting materials 3-methylmercapto propanal (produced from 2-propenal and methyl mercaptan), hydrocyanic acid (hydrogen cyanide), ammonia, and carbon dioxide are reacted to obtain 5-(2-methylmercaptoethyl) hydantoin (methionine hydantoin). Subsequently, this substance is hydrolyzed with potassium carbonate and potassium bicarbonate to obtain potassium methionate. Methionine is finally liberated from its potassium salt by treatment with carbon dioxide and can be filtered off as a precipitate from the mother liquor containing potassium carbonate and potassium bicarbonate. The reagents ammonia, potassium carbonate, and potassium bicarbonate, and carbon dioxide are generally recycled in the production of industrial methionine. Instead of the above-mentioned potassium compounds, the corresponding sodium compounds can also be used in this reaction. However, it is necessary to sometimes partially replace the aqueous mother liquor of this hydantoin hydrolysis cycle with fresh potassium hydroxide or fresh sodium hydroxide and basically remove (``purge'') the inactivated potassium salt or sodium salt from the cycle in the form of neutral potassium formate or sodium formate. This potassium formate or sodium formate is formed from the hydrogen cyanide and the residues of the potassium salt or sodium salt from the hydantoin hydrolysis present in the methionine hydantoin solution.

[0006] The so-called purge solution thus obtained usually contains, in addition to large amounts of potassium salts or sodium salts (generally about 6 to 14% by weight of potassium in the form of potassium salts), about 2 to 6% by weight of methionine and about 2 to 8% by weight of MetMet. The water content of this by-product is usually 70 to 80% by weight. Since it contains potassium, nitrogen and sulfur, this by-product is suitable as a liquid fertilizer. However, it is desirable that the MetMet contained in the by-product can be recovered to enhance the overall efficiency of the process.

[0007] Attempts to directly utilize MetMet from this by-product have so far failed. This is because classical isolation methods such as crystallization result in products of insufficient purity. Specific problems in isolating MetMet from the by-product are substances contained in significant amounts in the by-product, especially alkali metal ions such as potassium and bicarbonate ions. In addition, organic compounds present in the by-product have also been found to be an obstacle to isolating MetMet in pure form directly from the medium.

[0008] Accordingly, an object of the present invention is to provide a method for enabling the utilization of MetMet from such by-products or from aqueous media containing other MetMet and potassium, optionally further interfering substances, and a specific object was to recover MetMet in a sufficiently pure form from such media.

[0009] Surprisingly, it has been found that the object of the present invention can be solved by converting MetMet contained in an aqueous solution into a water-insoluble methionine diketopiperazine according to formula (II) (3,6-bis[2-(methylthio)ethyl]-2,5-piperazinedione; "Met-DKP").

Chemical formula

[0010] The water-insoluble Met-DKP can then be easily crystallized from the aqueous solution and isolated.

[0011] Accordingly, a first subject of the present invention is a method for recovering MetMet from an aqueous alkali metal ion-containing medium containing alkali metal ions, preferably potassium or sodium ions, in an amount of at least 1% by weight, characterized in that MetMet contained in the medium is converted to Met-DKP, and then Met-DKP is crystallized or precipitated and then separated, and the separation is preferably carried out by filtration, centrifugation and / or decantation.

[0012] According to the present invention, the conversion of MetMet to Met-DKP is preferably carried out by heating the medium to a temperature of 120 to 200 °C, particularly 150 to 180 °C, preferably 155 to 175 °C, more preferably 160 to 170 °C. The reaction is preferably carried out in a pressure vessel, particularly an autoclave, such that pressure is generated by heating, and the pressure during the reaction is preferably 2 to 12 bar, more preferably 4 to 10 bar, particularly 5 to 7 bar. The reaction is preferably carried out for 0.5 to 10 hours, more preferably 1 to 6 hours, particularly 2 to 5 hours.

[0013] The reaction functioned best at a pH of 3 to 7. Accordingly, according to the present invention, the medium preferably has a pH of 3 to 7, more preferably 3.5 to 6, particularly preferably 4.0 to 5.5, measured using a pH electrode at 20 °C.

[0014] Alkali metal ions contained in the by-products of the chemical methionine production process usually have an alkaline pH, particularly a pH of 7.5 to 12.5, more preferably 8 to 10, measured using a pH electrode at 20 °C. Therefore, the method of the present invention preferably includes, as a further step, the acidification of such a starting medium, and by the acidification, a pH of preferably 3 to 7, particularly 3.5 to 6, more preferably 4.0 to 5.5 is adjusted.

[0015] The acidification is preferably carried out using an acid selected from phosphoric acid, acetic acid, formic acid, sulfuric acid or mixtures thereof.

[0016] The aqueous medium containing alkali metal ions from which MetMet is recovered is preferably a composite matrix, especially a by-product and / or waste stream of a chemical methionine production process.

[0017] The alkali metal ions contained in the aqueous medium are preferably selected from potassium ions, sodium ions and mixtures thereof, more preferably potassium ions.

[0018] The aqueous medium is preferably an aqueous solution, but may also be an aqueous suspension.

[0019] The water content of the aqueous medium used in this process is preferably 50 - 90% by weight, more preferably 60 - 85% by weight, especially 70 - 80% by weight, that is, the total dry matter content is preferably 10 - 50% by weight, more preferably 15 - 40% by weight, especially 20 - 30% by weight.

[0020] The aqueous medium used in this process preferably contains MetMet in an amount of 5 - 20% by weight, preferably 8 - 16% by weight, based on the total dry matter content of the aqueous medium. Overall, the aqueous medium preferably contains MetMet in an amount of 1 - 12% by weight, preferably 2 - 8% by weight, more preferably 3 - 7% by weight.

[0021] The aqueous medium further contains alkali metal ions, preferably potassium ions or sodium ions, especially potassium ions. In particular, 10 - 50% by weight, more preferably 15 - 40% by weight, especially 20 - 35% by weight of alkali metal ions are present in the medium in the form of alkali metal salts, based on the total dry matter content of the aqueous medium. Overall, the aqueous medium preferably contains alkali metal ions, especially potassium or sodium ions, in the form of alkali metal salts, in an amount of at least 2% by weight, especially 2 - 18% by weight, more preferably at least 4% by weight, especially 4 - 16% by weight, especially at least 6% by weight, especially 6 - 14% by weight.

[0022] The aqueous medium preferably further contains a hydrogen carbonate, in particular 5 to 40% by weight, more preferably 10 to 35% by weight, especially 15 to 30% by weight of hydrogen carbonate, based on the total dry matter content of the aqueous medium. Overall, the aqueous medium preferably contains the hydrogen carbonate in an amount of at least 1% by weight, in particular in an amount of 1 to 15% by weight, more preferably in an amount of at least 2% by weight, in particular in an amount of 2 to 12% by weight, especially in an amount of at least 3% by weight, in particular in an amount of 3 to 10% by weight.

[0023] The aqueous medium more preferably further contains methionine, also preferably in an amount of 1 to 10% by weight, preferably in an amount of 2 to 6% by weight.

[0024] The amount of the aforementioned organic substances is preferably determined by HPLC, in particular the HPLC more specifically disclosed in the examples. The amount of potassium is preferably determined by IC (ion chromatography), in particular the IC more specifically disclosed in the examples. The amount of hydrogen carbonate is preferably determined by titration with hydrogen chloride.

[0025] Typical methionine by - product streams used for utilizing MetMet preferably have a pH value of 7.5 to 12.5, more preferably 8 to 10. Acidification of the medium is preferably carried out by slowly adding an acid such as phosphoric acid, acetic acid, formic acid or sulfuric acid (30% - 96%) while constantly stirring until the pH reaches 3 to 7, preferably 3.5 to 6. Most preferably, sulfuric acid is used to acidify the medium. Typically, foaming and a temperature increase are observed, which depend on the acid source used.

[0026] As a next step, preferably after 5 to 60 minutes, more preferably after 5 to 30 minutes, the reaction matrix is preferably transferred to an autoclave, the reaction mixture is sealed, and then preferably constantly stirred and heated to 150 to 180 °C, preferably 160 to 170 °C. Once the desired internal temperature is reached, the reaction mixture is preferably stirred for a further 0.5 to 3 hours, more preferably 1 to 2 hours, and then preferably cooled to a temperature of about 70 °C. The crystallization of Met-DKP is preferably already initiated by reducing the pressure in the reaction vessel. The resulting slurry is preferably filtered, and the obtained solid may be washed with distilled water. Next, this solid can be used directly to recover MetMet. Alternatively, the solid can also be dried.

[0027] In one preferred embodiment of the present invention, the method includes, before converting MetMet to Met-DKP, first removing most, preferably most (i.e., at least 50%) of the alkali metal ions from the medium. This is preferably done by using sulfuric acid for acidification of the alkaline starting medium and adjusting the pH value to 3 to 7, in particular 4 to 6, preferably 4 to 5, whereby the alkali metal ions contained in the medium precipitate in the form of alkali metal sulfates. The thus obtained alkali metal sulfates can then be separated by filtration or decantation. By doing so, preferably at least 50% by weight of the alkali metal ions already contained in the medium are removed. As a next step, after optionally further lowering the pH, the medium can be heated under pressure as previously disclosed to enable the formation of Met-DKP. The advantage of this method is that by removing the interfering alkali metal ions first, Met-DKP can be obtained directly in a very pure form, so that the alkali metal ions or their salts do not interfere with the formation of the Met-DKP precipitate.

[0028] In an alternative embodiment of the present invention, an intermediate step for removing alkali metal ions contained in the aqueous medium is not used, but the medium obtained after acidification is used directly in a pressure vessel for producing Met-DKP. This can result in the formation of a Met-DKP precipitate containing a larger amount of an alkali metal salt such as an alkali metal sulfate. However, surprisingly, it has been found that the alkali metal sulfate contained in the Met-DKP precipitate can be separated quite easily by washing with water or an aqueous solution. Therefore, this alternative method is also commercially feasible for obtaining sufficiently pure Met-DKP.

[0029] In a further preferred embodiment of the present invention, an acid is used for acidifying the alkali starting medium to form an alkali metal salt having higher water solubility, such as acetic acid, formic acid or phosphoric acid. The advantage of this method is that the alkali metal salt or at least most of it remains in a soluble form, and thus Met-DKP can be obtained directly in a relatively pure form in high yield without the need for an intermediate separation of alkali metal ions and without the need for subsequent elaborate purification steps.

[0030] The water-insoluble Met-DKP formed in the reaction can be easily crystallized or precipitated and isolated from the aqueous medium, preferably by filtration, centrifugation or decantation. The crystallization or precipitation is preferably carried out at a temperature of 0 to 140 °C, more preferably at a temperature of 20 to 100 °C. Thereafter, the obtained Met-DKP can be further purified, preferably by washing with water or an aqueous solution and / or by recrystallization.

[0031] As a next step, the Met-DKP thus obtained can be utilized in various ways, such as by reconverting it back to MetMet again, in particular recycling the Met-DKP into the MetMet process, or by further hydrolyzing it to obtain methionine.

[0032] The conversion of Met-DKP to MetMet can be carried out by acidic or basic hydrolysis.

[0033] Acidic hydrolysis is preferably carried out in the presence of an acid selected from the group consisting of mineral acids, HCl, H 2 CO 3 CO 2 / H 2 O, H 2 SO 4 phosphoric acid, carboxylic acids and hydroxycarboxylic acids.

[0034] Basic hydrolysis is preferably carried out at a pH of 7 - 14, particularly at a pH of 9 - 12, especially at a pH of 10 - 11 to obtain DL-methionyl-DL-methionine. Furthermore, preferably, a basic condition can be adjusted by using a substance selected from the group consisting of nitrogen-containing bases, NH 4 HCO 3 (NH 4 ) 2 CO 3 NH 4 OH / CO 2 mixture, carbamate, KHCO 3 K 2 CO 3 carbonates, alkali metal and alkaline earth metal bases.

[0035] Acidic or basic hydrolysis is preferably carried out at a temperature of 50 °C to 200 °C, preferably 80 °C to 180 °C, particularly preferably 90 °C to 160 °C. To avoid the conversion of Met-DKP to methionine, the acid or base is preferably added in a substantially equal molar amount, that is, 1 - 1.2 mol of acid or base equivalent per 1 mol of Met-DKP. Furthermore, the residual amount of Met-DKP is preferably detected analytically, and when no more Met-DKP can be detected in the aqueous medium, the reaction is stopped by cooling.

Example

[0036] Example 1: Acidification of the methionine side-stream solution by pH shift using sulfuric acid 100 g of a methionine side-stream solution (3.2 wt% Met) containing 3.7 wt% MetMet (1.9 wt% DDLL-MetMet, 1.8 wt% DLLD-MetMet) with a measured pH value of 9.9 and a total K content of 97.4 g / kg is acidified by slowly adding concentrated sulfuric acid (11.6 g, 96%) while stirring constantly at room temperature until a pH of 4 is reached. Typical foaming behavior and a temperature rise up to about 40 °C are observed. After 10 minutes, the resulting precipitate is recovered and characterized as potassium sulfate by IC analysis. The remaining mother liquor (84.5 g) is used for further conversion in Example 3.

[0037] Example 2: Acidification of the methionine side-stream solution with sulfuric acid to improve the precipitation of potassium sulfate 500 g of a methionine side-stream solution with a measured pH value of 9.4 (total K content 103.2 g / kg) is acidified by slowly adding concentrated sulfuric acid (53.6 g, 96%) while stirring constantly at room temperature until a pH of 5 is reached. Typical foaming behavior and a temperature rise up to about 45 °C are observed. The suspension is then cooled to 10 °C and after 15 minutes, the resulting precipitate is recovered and characterized as potassium sulfate by IC analysis. The remaining mother liquor can be used for further conversion as described in the following examples.

[0038] Example 3: Synthesis and isolation of Met-DKP from the methionine side-stream solution 84.5 g of the remaining mother liquor from Example 1 is transferred to a suitable autoclave, sealed, and then the reaction mixture is stirred constantly and heated to 160 °C. When the desired internal temperature (pressure about 6 bar) is reached, the reaction is stirred for a further 2.5 hours and then cooled to 70 °C within 1 hour. The resulting slurry is filtered and the obtained solid is washed with 25.0 g of distilled water. The solid is dried at 50 °C overnight to obtain 2.2 g of Met-DKP in a 52% yield (purity 82%).

[0039] Example 4: Acidification of the methionine side-stream solution by pH shift using acetic acid and isolation of Met-DKP A 100 g methionine side stream solution (3.0 wt% Met) containing 3.3 wt% MetMet (1.6 wt% DDLL-MetMet, 1.7 wt% DLLD-MetMet) with a measured pH value of 8.3 and a total K content of 93.1 g / kg is acidified by slowly adding glacial acetic acid (30.8 g, 99%) while constantly stirring at room temperature until a pH of 5 is reached. Only gentle foaming behavior is observed, and no temperature increase or precipitation is observed. After 5 minutes, 123.5 g of the solution is transferred to a suitable autoclave, sealed, and then the reaction mixture is constantly stirred and heated to 160 °C. When the desired internal temperature (pressure of about 6 bar) is reached, the reaction is stirred for an additional 2.5 hours and then cooled to 70 °C within 1 hour. The resulting slurry is filtered and the obtained solid is washed with 24.8 g of distilled water. The solid is dried at 50 °C overnight to obtain 1.5 g of Met-DKP in a 46% yield (purity 96%).

[0040] Example 5: Acidification of Methionine Side Stream Solution by pH Shift Using Sulfuric Acid and Isolation of Met-DKP A 100 g methionine side stream solution (3.0 wt% Met) containing 3.3 wt% MetMet (1.6 wt% DDLL-MetMet, 1.7 wt% DLLD-MetMet) with a measured pH value of 8.3 and a total K content of 93.1 g / kg is acidified by slowly adding concentrated sulfuric acid (8.7 g, 96%) while constantly stirring at room temperature until a pH of 5.5 is reached. Typical foaming behavior and a temperature increase up to 38 °C are observed. After 10 minutes, 100.1 g of the resulting slurry is transferred directly to a suitable autoclave, sealed, and then the reaction mixture is constantly stirred and heated to 160 °C. When the desired internal temperature (pressure of about 6 bar) is reached, the reaction is stirred for an additional 2.5 hours and then cooled to 70 °C within 40 minutes. The resulting slurry is filtered and the obtained solid is washed with 27.4 g of distilled water. The solid is dried at 50 °C overnight to obtain 5.7 g of Met-DKP in an 87% yield (purity 45%).

[0041] Example 6: Acidification of Concentrated and Methionine-Reduced Side Stream Solution by pH Shift Using Sulfuric Acid and Isolation of Met-DKP 100 g of a methionine-reduced sidestream solution (2.1 wt% Met) containing 6.5 wt% MetMet (3.4 wt% DDLL-MetMet, 3.1 wt% DLLD-MetMet) with a measured pH value of 8.8 and a total K content of 130.0 g / kg is acidified by slowly adding concentrated sulfuric acid (11.3 g, 96%) while stirring constantly at room temperature until a pH of 4.5 is reached. Typical foaming behavior and a temperature rise up to 40 °C are observed. After 10 minutes, 102.7 g of the resulting slurry is transferred directly to a suitable autoclave, sealed, and then the reaction mixture is stirred constantly and heated to 170 °C. When the desired internal temperature (pressure about 6 bar) is reached, the reaction is stirred for an additional 1 hour and then cooled to 70 °C within 50 minutes. The resulting slurry is filtered and the obtained solid is washed with 30.0 g of distilled water. The solid is dried at 50 °C overnight to obtain 18.3 g of Met-DKP in 77% yield.

[0042] Example 7: Acidification of Methionine Sidestream Solution by pH Shift Using Formic Acid and Isolation of Met-DKP 100 g of a methionine sidestream solution (3.2 wt% Met) containing 3.7 wt% MetMet (1.9 wt% DDLL-MetMet, 1.8 wt% DLLD-MetMet) with a measured pH value of 9.9 and a total K content of 97.4 g / kg is acidified by slowly adding formic acid (9.7 g, 99%) while stirring constantly at room temperature until a pH of 5.5 is reached. A decrease in foaming behavior is observed and no significant temperature rise up to 24 °C is observed. After 10 minutes, 103.4 g of a nearly clear solution is transferred directly to a suitable autoclave, sealed, and then the reaction mixture is stirred constantly and heated to 160 °C. When the desired internal temperature (pressure about 5 bar) is reached, the reaction mixture is stirred for an additional 2.5 hours and then cooled to 70 °C within 40 minutes. The resulting slurry is filtered and the obtained solid is washed with 25.0 g of distilled water. The solid is dried at 50 °C overnight to obtain 1.7 g of Met-DKP in 43% yield (88% purity).

[0043] Example 8: Acidification of Methionine Sidestream Solution by pH Shift Using Phosphoric Acid and Isolation of Met-DKP 100 g of a methionine side-stream solution (3.0 wt% Met) containing 3.3 wt% MetMet (1.6 wt% DDLL-MetMet, 1.7 wt% DLLD-MetMet) with a measured pH value of 8.3 and a total K content of 93.1 g / kg is acidified by slowly adding phosphoric acid (19.9 g, 85%) while stirring constantly at room temperature until a pH of 5.0 is reached. Typical foaming behavior and a temperature rise up to 32 °C are observed. After 10 minutes, 112.1 g of the resulting slurry is transferred directly to a suitable autoclave, sealed, and then the reaction mixture is stirred constantly and heated to 160 °C. When the desired internal temperature (pressure of about 5 bar) is reached, the reaction is stirred for an additional 2.5 hours and then cooled to 70 °C within 40 minutes. The resulting slurry is filtered and the obtained solid is washed with 28.2 g of distilled water. The solid is dried at 50 °C overnight to obtain 2.9 g of Met-DKP in a yield of 75% (purity 80%).

[0044] Example 9: Acidification of a methionine side-stream solution by pH shift using dilute sulfuric acid and isolation of Met-DKP 100 g of a methionine side-stream solution (3.0 wt% Met) containing 3.3 wt% MetMet (1.6 wt% DDLL-MetMet, 1.7 wt% DLLD-MetMet) with a measured pH value of 8.3 and a total K content of 93.1 g / kg is acidified by slowly adding dilute sulfuric acid (28.5 g, 30%) while stirring constantly at room temperature until a pH of 5.5 is reached. A decrease in foaming behavior and a temperature rise up to 28 °C are observed. After 10 minutes, 121.7 g of the resulting slurry is transferred directly to a suitable sealed autoclave, the reaction mixture is stirred constantly, and heated to 160 °C. When the desired internal temperature (pressure of about 5 bar) is reached, the reaction is stirred for an additional 2.5 hours and then cooled to 70 °C within 45 minutes. The resulting slurry is filtered and the obtained solid is washed with 27.0 g of distilled water. The solid is dried at 50 °C overnight to obtain 4.9 g of Met-DKP in a yield of 64% (purity 40%).

[0045] Example 10: Acidification of a methionine side-stream solution by pH shift using sulfuric acid and isolation of Met-DKP A 100 g methionine side-stream solution (4.1 wt% Met) containing 3.9 wt% MetMet (1.8 wt% DDLL-MetMet, 2.1 wt% DLLD-MetMet) with a measured pH value of 9.4 and a total K content of 103.2 g / kg is acidified by slowly adding concentrated sulfuric acid (3.6 g, 96%) while constantly stirring at room temperature until a pH of 8.0 is reached. A decrease in foaming behavior and a temperature increase up to 31 °C are observed. After 10 minutes, 100.5 g of the resulting slurry is transferred directly to a suitable autoclave, sealed, and then the reaction mixture is constantly stirred and heated to 160 °C. When the desired internal temperature (pressure about 7 bar) is reached, the reaction mixture is stirred for an additional 2.5 hours and then cooled to 70 °C within 45 minutes. The resulting slurry is filtered and the obtained solid is washed with 27.5 g of distilled water. The solid is dried at 50 °C overnight to obtain 2.0 g of an undefined solid (Met-DKP yield < 1 wt%). HPLC analysis revealed that only about 6 wt% of MetMet was converted to Met-DKP.

[0046] Example 11: Attempt to isolate Met-DKP using methionine side-stream solution directly A 100 g methionine side-stream solution (3.2 wt% Met) containing 3.4 wt% MetMet (1.6 wt% DDLL-MetMet, 1.8 wt% DLLD-MetMet) with a measured pH value of 8.4 and a total K content of 88.8 g / kg is transferred directly to a suitable autoclave, sealed, and then the reaction mixture is constantly stirred and heated to 160 °C. When the desired internal temperature (pressure about 7 bar) is reached, the reaction mixture is stirred for an additional 2.5 hours and then cooled to 70 °C within 30 minutes. The resulting slurry is filtered and an attempt is made to wash the obtained solid with 23.7 g of distilled water. Unfortunately, no solid remained for drying and analysis after the first washing step. HPLC analysis revealed that only about 1 wt% of MetMet was converted to Met-DKP.

[0047] Analysis method High-performance liquid chromatography (HPLC): The quantification of D,L-Met, DDLL-MetMet, DLLD-MetMet, DDLL-Met-DKP and DLLD-Met-DKP was performed after calibration with their respective reference substances using an isocratic HPLC method. All analyses were carried out on an Agilent 1260 Infinity II device equipped with an HPLC pump G7112B, a VWD detector G7114A and a column thermostat G7116A. A standard RP 18 column (Altima C18, 5 mm, length 25 cm, 40 °C) was used for separation, and an eluent system consisting of 900 g of deionized water, 70 g of acetonitrile and 40 g of phosphoric acid (85%) was flowed at a flow rate of 1 ml / min for an elution time of 35 min. The detection wavelength was set at 210 nm. For sample preparation, 20 - 100 mg was weighed into a volumetric flask, filled with the eluent system to exactly 100 ml, and degassed in an ultrasonic bath before injection.

[0048] Ion chromatography (IC): The total potassium content (total K content) in the initial aqueous potassium-containing medium was measured by IC after calibration with a reference substance. All analyses were carried out on a Metrohm 882 Compakt IC Plus system equipped with a Methrom 850 Professional IC Detektor LF unit and Metrohm Metrosep C6 250 / 4.0 and Methrom Metrosep C6 Guard / 4.0 pre-columns. A pure aqueous eluent system containing 1.7 mmol / l nitric acid, 1.7 mmol / l dipicolinic acid and 2.5% (v / v) acetonitrile was used, and this system was flowed at a flow rate of 1 ml / min at room temperature. For sample preparation, an appropriate amount of the substance was weighed into a volumetric flask, filled with a 2.5 mmol / l nitric acid solution to exactly 100 ml, and degassed in an ultrasonic bath before injection.

Claims

1. A method for recovering methionylmethionine from an aqueous alkali metal ion-containing medium containing at least 1% by weight of alkali metal ions, characterized by converting the methionylmethionine contained in the aqueous medium to bis(methionyl)-diketopiperazine, and then crystallizing or precipitating the bis(methionyl)-diketopiperazine before separation.

2. The method according to claim 1, characterized in that the medium is heated to a temperature of 120 to 200°C in a sealed pressure vessel for the conversion of methionylmethionine to bis(methionyl)-diketopiperazine.

3. The method according to claim 2, characterized in that the reaction is carried out at a pressure of 2 to 12 bar.

4. The method according to claim 1, characterized in that the pH of the medium, as measured using a pH electrode at 20°C, is between 3 and 7.

5. The method according to claim 4, characterized in that the starting medium has a higher pH, and the pH is adjusted to 3 to 7 by acidifying the starting medium.

6. The method according to any one of claims 1 to 5, wherein the alkali metal ion is selected from potassium ions, sodium ions, and mixtures thereof.

7. The method according to any one of claims 1 to 5, wherein the aqueous medium contains methionylmethionine in an amount of 1 to 12% by weight.

8. The method according to any one of claims 1 to 5, wherein the aqueous medium contains alkali metal ions in an amount of 2 to 18% by weight.

9. The method according to any one of claims 1 to 5, wherein the aqueous medium contains methionine.

10. The method according to any one of claims 1 to 5, wherein the aqueous medium contains a bicarbonate.

11. The method according to any one of claims 1 to 5, wherein the aqueous medium is a composite matrix.

12. The method according to any one of claims 1 to 5, wherein, prior to the conversion of methionylmethionine to bis(methionyl)-diketopiperazine by reaction in a sealed pressure vessel, most of the alkali metal ions contained in the medium are separated by the formation of an insoluble alkali metal salt.

13. The method according to any one of claims 1 to 5, wherein the separation of the bis(methionyl)-diketopiperazine formed in the reaction is carried out by filtration, centrifugation and / or decantation.

14. The method according to any one of claims 1 to 5, wherein the bis(methionyl)-diketopiperazine is separated from the aqueous medium and then converted back to methionylmethionine by basic or acidic hydrolysis.

15. The method according to any one of claims 1 to 5, wherein the bis(methionyl)-diketopiperazine is separated from an aqueous solution and then converted to methionine by basic or acidic hydrolysis.