PROCESS FOR THE DIASTEREOMERICALLY PURE PREPARATION OF DL/LD-METHIONYLMETHIONINE

Abstract

The invention relates in particular to a process for the preparation of DL/LD-methionine diketopiperazine (I) characterized in that a DD/LL-methionylmethionine-containing aqueous solution or suspension, which has a pH of 3 to 7, measured using a pH electrode at 20 C., is reacted at a temperature of 150 to 220 C., preferably at 170 to 210 C., until an aqueous solution or suspension has formed containing at least a proportion of 30 mol %, preferably 50 mol %, especially 60 mol % of DL/LD-methionine diketopiperazine, based on the total content of DL/LD- and DD/LL-methionine diketopiperazine in the reaction mixture. This process forms part of an overall process for the preparation of DL/LD-methionylmethionine, which is obtained by hydrolysis from the DL/LD-methionine diketopiperazine (I) produced initially.

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Claims

1. A process for the preparation of DL/LD-methionine diketopiperazine (I), the process comprising: ##STR00006## reacting a DD/LL-methionylmethionine-containing aqueous solution or suspension, which has a pH of 4 to 7, measured using a pH electrode at 20 C., at a temperature of 150 to 220 C. until an aqueous solution or suspension has formed containing at least a proportion of 30 mol % of DL/LD-methionine diketopiperazine, based on the total content of DL/LD- and DD/LL-methionine diketopiperazine in the reaction mixture.

2. The process according to claim 1, wherein the aqueous solution or suspension has a pH of 4 to 6.

3. The process according to claim 1, wherein the reacting is at a temperature of 175 to 210 C.

4. The process according to claim 1, wherein the total concentration of DL/LD- and DD/LL-methionylmethionine equivalents in the form of DL/LD- and DD/LL-methionine diketopiperazine in the reaction mixture at the end of the reaction is in the range from 0.1% to 18% by weight.

5. The process according to claim 1, wherein a DD/LL-methionylmethionine-containing aqueous solution or suspension is used which already contains DL/LD-methionylmethionine.

6. The process according to claim 5, wherein the aqueous solution or suspension used already contains up to a proportion of 30 mol % of DL/LD-methionylmethionine based on its total content of DD/LL- and DL/LD-methionylmethionine.

7. A process for obtaining diastereomerically pure DL/LD-methionylmethionine, the process comprising: a. reacting methionine hydantoin together with alkali metal base to afford a diastereomeric mixture of DL/LD-methionine diketopiperazine and DD/LL-methionine diketopiperazine (DLLD-DKP and DDLL-DKP), b. crystallizing the DLLD-DKP and DDLL-DKP from a. by concentrating or cooling the reaction solution from a.; c. separating the DLLD-DKP and DDLL-DKP crystals from the DKP mother liquor; d. mixing the DLLD-DKP and DDLL-DKP separated crystals into water and the mixture is brought, by addition of appropriate amounts of alkali, to a pH of 10 to 14, measured using a pH electrode at 20 C., and is hydrolysed at a temperature of from 90 to 150 C. with a residence time of 30 to 180 min to give a corresponding aqueous solution or suspension of a diastereomeric mixture of DL/LD-methionylmethionine alkali metal salt and DD/LL-methionylmethionine alkali metal salt; e. adding an appropriate amount of acid to the solution or suspension from d. until the pH, measured at 20 C., is 7; f. evaporating water and/or cooling to produce a suspension which consists of a solids fraction, which predominantly contains DL/LD-methionylmethionine, and mother liquor, which predominantly contains DD/LL-methionylmethionine; g. separating the solids fraction from f. off from the mother liquor, h. alternatively washing and/or drying, with diastereomerically pure DLLD-methionylmethionine being obtained; i. reacting the remaining DD/LL-methionylmethionine-containing mother liquor from g. according to claim 1 so that an aqueous solution or suspension containing a diastereomeric mixture of DL/LD-methionine diketopiperazine and DD/LL-methionine diketopiperazine is formed having a proportion of up to 60 mol % DL/LD-methionine diketopiperazine based on the total content of DL/LD- and DD/LL-methionylmethionine equivalents in the reaction mixture; and j. recycling the reaction mixture of i. into step b.

8. The process according to claim 7, wherein in step d. 0.9 to 1.5 molar equivalents of base are used based on the total content of DL/LD- and DD/LL-methionylmethionine equivalents in the reaction mixture.

9. The process according to claim 7, wherein in step d. alkali metal hydroxides are used as base.

10. The process according to claim 7, wherein in step e. strong mineral acids are used.

11. The process according to claim 7, wherein in step f. the suspension is cooled to a temperature of 50 C.

12. The process according to claim 7, wherein the suspension produced in step f. contains at least 1% by weight, but not more than 15% by weight, total content of DD/LL- and DL/LD-methionylmethionine.

13. A process for producing an animal feed additive for aquacultures, the process comprising: adding a pulverulent, diastereomerically pure DL/LD-methionylmethionine-containing product to an animal feed additive, wherein the pulverulent, diastereomerically pure DL/LD-methionylmethionine-containing product comprises: a. at least 97% by weight total content of DD/LL- and DL/LD-methionylmethionine, b. at least 90 mol % DL/LD-methionylmethionine and at most 10 mol % DD/LL-methionylmethionine, preferably at least 95 mol % DL/LD-methionylmethionine and at most 5 mol % DD/LL-methionylmethionine, based in each case on the total content of DD/LL- and DL/LD-methionylmethionine, c. at most 1.0% by weight residual moisture, d. at most 2.0% by weight sulfate (ash) and e. a particle size distribution with a median D50 of 80 to 300 m, preferably 150 to 250 m.

14. A process for producing an animal feed additive for aquacultures, the process comprising: adding the pulverulent, diastereomerically pure DL/LD-methionylmethionine-containing product according to claim 13 to an animal feed additive.

Description

[0065] FIG. 1 shows the scheme for the preparation of DL/LD-methionylmethionine

[0066] The scheme comprises the following steps: [0067] a. reaction of methionine hydantoin with alkali metal base to give DLLD/DDLL-Met-DKP [0068] b. crystallization of DLLD/DDLL-Met-DKP [0069] c. separating-off of DLLD/DDLL-Met-DKP [0070] c1. discharge of DKP mother liquor [0071] c2. wastewater treatment [0072] d. alkaline hydrolysis of DLLD/DDLL-Met-DKP to DLLD/DDLL-Met-Met [0073] e. acidification and [0074] f. precipitation of DLLD-Met-Met [0075] g. separating-off of the solid DLLD-Met-Met [0076] h. washing and/or drying of DLLD-Met-Met [0077] h1. bagging of DLLD-Met-Met [0078] i. reaction and epimerization of DDLL-Met in DDLL-Met-containing mother liquor to give DLLD/DDLL-Met-DKP [0079] j. recycling of DLLD/DDLL-Met-DKP into step c.

[0080] FIG. 2 shows pH as a function of temperature measured in a DDLL-methionylmethionine-containing solution for the preparation of DL,LD-methionine diketopiperazine, said solution having a content of 3% by weight of DD,LL-methionylmethionine and being used thus in Industrial Example 10. This solution did not contain any KHCO.sub.3, in contrast to Comparative Example 12 which was conducted in accordance with WO 2010043558 A1, page 45a). Dispensing with a further additive (KHCO.sub.3) is additionally a great advantage with respect to the process from the WO document.

EXAMPLES

[0081] Unless otherwise stated, the examples were performed as per the general process description and in accordance with the respectively associated information in Table 1.

Analytical Methods

Determination of Bulk Density

[0082] The bulk density in kg/L was determined using a 1 L measuring cylinder, which was filled with the bulk material precisely to the 1000 ml mark, and was measured by weighing the weight of the contents so as to result in the bulk density directly.

Determination of Flow Characteristics

[0083] The flow characteristics (flowability) was determined by assigning a flow grade of 1 (very good) to 6 (unsatisfactory) on the basis of prior measurement of the flowability using standard glass orifice vessels. These had a cylindrical shape with a conical lower end in the centre of which an orifice was positioned (analogous to a silo) of differing width ranging from narrow for grade 1 to relatively wide for grade 6. The measurement was started with the narrowest orifice vessel, the orifice was kept closed with a glass plate, the orifice vessel was filled with the bulk material, the glass plate was removed and the outflow was assessed. Only when a virtually uninhibited outflow of the bulk material could be observed was a grade of 1 given. If this was not the case, the next-wider orifice vessel was used and a grade of 2 was assigned in the event of flawless outflow; if this was not the case once again, the next-wider orifice vessel was used, and so on up to the widest orifice vessel (vessel 5). Only material which could not flow uninhibited from this orifice vessel either was assessed with a grade of 6. The standard orifice vessels all had a height of the cylindrical portion of 70 mm and an internal width of 36 mm. The orifices had the following widths for vessel 1: 2.5 mm, vessel 2: 5 mm, vessel 3: 8 mm, vessel 4: 12 mm, vessel 5: 18 mm.

Determination of pH

[0084] Unless otherwise indicated, the pH was measured with a glass electrode in aqueous solution and at a temperature of 20 C.

[0085] The quantitative determination of the concentrations of Met, Met-Met, methionyl-DKP and so on was effected using standard HPLC methods against an external standard.

General Process Description of the DKP Synthesis

[0086] An aqueous solution of the dipeptide Met-Met, after adjusting the pH to 4.5 or 5 using either sulfuric acid or caustic soda, was heated to 150-180 C. for a period of 30-120 min. After cooling to 70 C. by reducing the pressure, an aqueous suspension was obtained. After filtering off and washing the filter cake with water, a solid was obtained which primarily contained DKP which consisted of a mixture of DLLD-DKP and DDLL-DKP in a ratio in the most favourable case of 50/50 or greater, independently of the stereochemical configuration of the starting material Met-Met.

Example 1 (Variation of pHBasic Conditions, Comparative Example)

[0087] By adjusting the pH to 9.3 and otherwise proceeding according to the general process description, primarily methionine was already formed at temperatures of 140 C. DKP was only obtained in a yield of 34% and with a diastereomeric ratio of 57/43 DLLD/DDLL-DKP, starting from a diastereomeric ratio of 36/64 DLLD/DDLL-Met-Met in the starting material.

Example 2 (Variation of pHAcidic Conditions, Comparative Example)

[0088] By adjusting the pH to 2.9 and otherwise proceeding according to the general process description, primarily methionine was already formed at temperatures of 140 C. DKP was only obtained in a yield of 60% and with a diastereomeric ratio of 36/64 DLLD/DDLL-DKP, starting from the same diastereomeric ratio of 36/64 DLLD/DDLL-Met-Met in the starting material.

Examples 3 to 5 (Variation of Temperature, Reaction Time and pH)

Example 3

[0089] Heating the mixture to 150 C., holding at this temperature for 120 min and then holding at 120 C. and pH 9.0 for 60 min and otherwise proceeding according to the general process description afforded DKP in 53% yield with significant epimerization. The ratio of the diastereomers shifted from 15/85 DLLD/DDLL-Met-Met to 60/40 DLLD/DDLL-DKP.

Example 4

[0090] In contrast, heating the mixture to 150 C., holding at this temperature for 120 min and pH 4.8 and otherwise proceeding according to the general process description afforded DKP in 80% yield with markedly less epimerization. The ratio of the diastereomers shifted from 15/85 DLLD/DDLL-Met-Met to 25/75 DLLD/DDLL-DKP.

Example 5

[0091] In contrast, heating the mixture to 160 C., holding at this temperature for 60 min and otherwise proceeding according to the general process description afforded DKP in 72% yield with significant epimerization. The ratio of the diastereomers shifted from 15/85 DLLD/DDLL-Met-Met to 39/61 DLLD-/DDLL-DKP.

Example 6

[0092] 1.47 kg of an aqueous solution having a content of 2.9% DDLL-Met-Met (151 mmol) and 0.9% DLLD-Met-Met (50 mmol) were adjusted to pH 4.5 by addition of 10% NaOH. The solution was then heated to a temperature of 170 C. (7 barg) as rapidly as possible and held at this temperature for 90 min. Once Met-Met could no longer be detected analytically, the reaction mixture was cooled down to 100 C. by decompression. The suspension thus obtained was cooled down further to 70 C. under vacuum. Filtering off the solid precipitate formed and washing the filter cake with 150 g of water afforded 98 g of brownish crystals. 43 g of a DKP mixture (161 mmol, 80% yield) composed of both diastereomers was isolated after drying in a ratio of DLLD-/DDLL-DKP of 48/52 with a chemical purity of 98%.

Examples 7 and 8 (Variation of the Reaction Time)

[0093] Shortening the reaction time to 60 min and otherwise proceeding according to the process description under Example 6 afforded a lower yield of 73% DKP with a diastereomeric ratio of 52/48 DLLD/DDLL-DKP, and with a 30 min reaction time afforded a yield of 71% with a diastereomeric ratio of 48/52.

Example 9 (Increasing the Reaction Temperature)

[0094] A further increase of the temperature to 175 C., holding for 30 min at this temperature and pH 4.5 and otherwise proceeding according to the process description under Example 6 again achieved a somewhat higher yield of 77% DKP compared to Example 8 with a diastereomeric ratio of 38/62 DLLD-/DDLL-DKP.

Example 10 (Reaction Temperature 1750 at pH 6.0)

[0095] Analogously to Example 6, an aqueous solution having a content of 2.7% Met-Met and a Met-Met starting ratio DLLD/DDLL of 12/88 and having a pH of 6.0 (Met-Met mother liquor from industrial production plant) was heated as rapidly as possible to a temperature of 175 C. and held at this temperature for 90 minutes. The procedure was otherwise as per the process description under Example 6. An even higher yield of 96% DKP was achieved and at the same time a highly favourable diastereomeric ratio of approx. 60/40 DLLD-/DDLL-DKP.

Example 11 (Reaction Temperature 1750 at pH 4.7)

[0096] Analogously to Example 10, an aqueous solution having a content of 3.3% Met-Met and a Met-Met starting ratio DLLD/DDLL of 25/75 and having a pH of 4.7 (Met-Met mother liquor from industrial production plant) was heated as rapidly as possible to a temperature of 175 C. and held at this temperature for 90 minutes. The procedure was otherwise as per the process description under Example 6. An even higher yield of 98% DKP was achieved and at the same time a highly favourable diastereomeric ratio of approx. 53/47 DLLD-/DDLL-DKP.

Example 12 (Variation of the pH, Comparative Example According to WO2010043558 A1, Page 45a))

[0097] Racemization of DL/LD-Methionylmethionine

[0098] 12.6 g (45.0 mmol) of DD/LL-methionylmethionine (Met-Met starting ratio DLLD/DDLL of 0/100) were dissolved, together with 4.5 g (45.0 mmol) of KHCO.sub.3, in 75 ml of water in a 200 ml Roth laboratory reactor and heated to 160 C. with stirring. The pressure rose to 7 bar, and after 6 hours at this temperature the autoclave was cooled in an ice bath to 20 C. and the pH was determined in the obtained suspension to be pH=9.1 using a glass electrode. The suspension was then filtered, the solid filtered off was washed multiple times with water and dried at 50 C. under reduced pressure in a drying cabinet. The yield isolated was 6.0 g (22.9 mmol) (51%) of bis[2-(methylthio)ethyl]-2,5-piperazinedione (Ill), yellowish-white crystals, purity >98% (HPLC), melting point 233-236 C.; diastereomeric ratio: 54:46 (DD/LL-III:meso-III). The washing water and the mother liquor were combined and concentrated to a volume of 25 ml on a rotary evaporator at 40 C. A moderate CO.sub.2 stream was then introduced into the solution obtained until a pH of 6.0 was achieved and a white solid precipitated out. This solid was filtered off, washed with a little cold water, and dried overnight in a vacuum drying cabinet at 50 C. The yield isolated was 5.5 g (19.6 mmol) (44%) of DD/LL/DL/LD-methionylmethionine (I), white solid, purity >98% (HPLC).

Example 13 (Hydrolysis of DLLD/DDLL-Met-DKP to DLLD/DDLL-Met-Met Etc.)

[0099] The diastereomeric mixtures of DLLD/DDLL-Met-DKP produced according to Examples 10 and 11 could be hydrolysed according to steps e. to h. (see above and FIG. 1) to the corresponding mixtures of DLLD/DDLL-Met-Met alkali metal salts. After appropriate acidification with, for example, sulfuric acid to pH 4.5 to 5.6, DLLD-Met-Met was precipitated as solid, filtered off, washed and dried. The DLLD-Met-Met thus obtained consistently exhibited flow grades of 1 to 2, bulk densities of >600 kg/m.sup.3, and low dust contents of approx. 10% <63 m. The minimum ignition energies found for these products were above 10 mJ at room temperature and even at 100 C. were still above 3 mJ.

[0100] The mother liquor from the filtration, with the DDLL-Met-Met remaining in solution, could then be supplied to step i. of cyclization and epimerization.

TABLE-US-00001 TABLE 1 Overview of the examples Met- Met-Met DKP Met starting end Reaction conc. DKP ratio ratio Starting material/ time Temp. [% by Yield DLLD/ DLLD/ Example type of reaction [min] [ C.] pH wt.] [%] DDLL DDLL 1 Met-Met mother 120 140 9.3 10.5 34 36/64 57/43 (comparison) liquor/epimerization under basic conditions 2 Met-Met mother 120 140 2.9 8.9 60 36/64 36/64 (comparison) liquor/epimerization under acidic conditions 3 Met-Met mother 120 150 4.5 3.4 53 15/85 60/40 liquor/cyclization and 60 120 9.0 epimerization at IP (isoelectric point), followed by basic conditions 4 Met-Met mother 120 150 4.8 3.4 80 15/85 25/75 liquor/epimerization at IP 5 Met-Met mother 60 160 4.5 3.4 72 15/85 39/61 liquor/epimerization at IP 6 Met-Met mother 90 170 4.5 3.4 81 15/85 48/52 liquor/epimerization at IP 7 Met-Met mother 60 170 4.5 3.4 73 15/85 52/48 liquor/epimerization at IP 8 Met-Met mother 30 170 4.5 3.4 71 15/85 48/52 liquor/epimerization at IP 9 Met-Met mother 30 175 4.5 3.4 77 15/85 38/62 liquor/epimerization at IP 10 Met-Met mother 90 174 6.0 2.7 96 12/88 60/40 liquor/production epimerization at pH 6.0 11 Met-Met mother 90 174 4.7 3.3 98 25/75 53/47 liquor/production epimerization at pH 4.7 12 Comparative example 360 160 9.1 13.7 51 0/100 46/54 according to WO2010043558 A1, page 45a), Mixture of DDLL-Met-Met, KHCO.sub.3 and H.sub.2O