WO2022144293A1

WO2022144293A1 - Process for producing particulate methionylmethionine

Info

Publication number: WO2022144293A1
Application number: PCT/EP2021/087453
Authority: WO
Inventors: Tobias Winkler; Jörg HEIDERHOFF; Sascha Braune
Original assignee: Evonik Operations Gmbh
Priority date: 2020-12-30
Filing date: 2021-12-23
Publication date: 2022-07-07
Also published as: EP4023662A1

Abstract

The invention relates to a process for producing readily filterable particles of DL/LD-methionylmethionine, characterized in that a stream of aqueous solution or suspension containing DL/LD-methionylmethionine alkali metal salt is mixed with a dilute aqueous mineral acid solution so that, within a mixing time of at most 5000 milliseconds, preferably at most 3000 milliseconds, a suspension is formed having a pH of 4 to 6, the pH being measured using a glass electrode directly in the suspension at 20°C. 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 produced initially.

Description

Process for producing particulate methionylmethionine

Document WO2010043558 A1 already discloses a process for the preparation of methionylmethionine (Met- Met), the homologous dipeptide of DL-methionine, which increasingly finds use primarily as a high-value methionine source for the feeding of fish and crustaceans kept in aquacultures.

In this context, the invention relates to a process for producing readily filterable particles of methionylmethionine (Met-Met) with the DLLD configuration.

Due to its two stereocentres (two asymmetrical carbon atoms), the product exists in the form of two diastereomers, DL,LD-Met-Met and DD,LL-Met-Met, that is to say in the form of two configurationally isomeric enantiomer pairs, which can both be utilized well by the animals but which possess markedly different physical properties which in practical handling can lead to certain problems.

It has been found that the two diastereomers form different crystal structures. While DLLD-Met-Met forms a spherical agglomerate in the end product precipitation, DDLL-Met-Met crystallizes out in the form of needles. This is associated with differing flowability and tendency to clumping, and also differing solubility.

While DLLD-Met-Met at room temperature has a water solubility of just 0.4 g/l, the water solubility of DDLL-Met-Met is much higher at 21 .0 g/l. However, a high water solubility is rather unfavourable for use in aquacultures since losses of substances of value can arise as a result of leaching from the feed pellet. The product from the preparation process according to WO2010043558 A1 typically has a DLLD-/DDLL-Met-Met ratio of 60/40. A product having a much higher proportion of DLLD- Met-Met would therefore be desirable. In addition, the product known to date exhibits relatively low bulk densities of at most 500 kg/m³, only moderate to relatively poor flowabilities of 5 (poor) to 6 (inadequate), and a relatively low minimum ignition energy (MIE) of < 3 mJ, and is therefore comparatively highly flammable, and hence these properties also appear to be in need of improvement.

Met-Met has been produced by the process according to WO2010043558A1 for some time, this being commercially available under the product name AQUAVI® Met-Met.

In this process, the fractional crystallization of the two diastereomeric enantiomer pairs on the industrial scale is a key step for the downstream process steps.

Product properties that are important to the user are primarily the flowability and the dustiness/the dust content of the product. A poor flowability of the solid leads to the clogging of lines, hoppers, conveying devices or other equipment when transferring or metering into the feedstuff. A high dust content of the product is accompanied by a reduction in the minimum ignition energy on account of the greater surface area. Dust refers, inter alia, in safety technology, to particles which are smaller than 63 pm. Each of these, both the average to poor handling properties and the classification as extremely sensitive to ignition due to a minimum ignition energy of below 3 mJ, can result in the manufacturer of feed mixtures having to adapt or upgrade their plants in order to be able to safely convey the product, or convey it at all, for example by establishing explosion protection zones. These additional investments can deter customers from a product.

The present invention relates to a process regime for the precipitation of Met-Met which results in a crystalline solid having very good handling properties and a greatly reduced dust content.

The "crystallization" of the less soluble enantiomer pair, the DLLD-Met-Met, is not a crystallization in the conventional sense, but rather a precipitation. Precipitations cannot be described using the rules of a crystallization.

The precipitation of the DLLD-Met-Met is induced by adjustment of the pH to approximately 5 at a temperature above 50°C, which corresponds to the isoelectric point of the dipeptide. This can be achieved, as described in the above-mentioned WO application, by increasing the pH of an ammonium salt solution of Met-Met using a base or by lowering the pH by adding acid. However, the quality of the particles fluctuates greatly depending on the process regime. For instance, direct addition of sulfuric acid to a concentrated solution of the sodium salt of the dipeptide (NaMetMet) results in a very fine precipitate which can be separated off and conveyed only with difficulty.

It was an object of the present invention in particular to provide a robust, continuously performable process for the precipitation of Met-Met within a process for preparing Met-Met, this precipitation process resulting in a product which no longer exhibits the disadvantages of the product to date, such as dustiness and low minimum ignition energy, and moreover has good handling properties such as a good flowability.

Surprisingly, it has now been found that very good agglomerates of the DLLD-Met-Met can be produced when the alkali metal-Met-Met solution is diluted drastically in a dilute acid, such as sulfuric acid (or recycled mother liquor), adjusted to a pH of 2 to 3, and the pH is raised to a pH of approximately 5 with further addition of the alkali metal-Met-Met solution. Once a pH of 5 is reached, a further increase in the pH must be compensated by the simultaneous addition of acid, in this case sulfuric acid. Exceeding a pH of 6 or an inverse reaction regime inevitably results in a very fine and hard to filter solid, and must be avoided. So long as the pH varies within a range between 4 and 6, little to no effect on product quality can be observed. This has the effect of placing particular requirements on the mixing-in of the acid. In contrast, the manner in which the alkali metal-Met-Met solution, which itself has a pH of 11 to 14, generally of approximately 12, is mixed in has a decisive influence on the success of the precipitation. If, for example, the mixing of the alkali metal-Met-Met solution is not optimal, for example if the alkali metal-Met-Met salt passes through the pH range from approximately pH 12 to approximately pH 5 too slowly, very fine to amorphous particles are generated. This can no longer be corrected after the event. For example, dissolution by addition of sodium hydroxide solution, by way of peptide cleavage taking place at least to some extent, would also lead to an undesired increase in the methionine content which would no longer be able to be sufficiently lowered after a second crystallization.

The present invention therefore provides a process for producing readily filterable particles of DL/LD-methionylmethionine (la + lb),

enantiomer (I b) characterized in that a stream of aqueous solution or suspension containing DL/LD- methionylmethionine alkali metal salt and typically having a pH of 11 to 14 is mixed with a dilute aqueous mineral acid solution typically having a pH of 1 to 4 so that, within a very short mixing time of at most 5000 milliseconds, preferably at most 3000 milliseconds, a suspension is formed having a pH of 4 to 6, the pH being measured using a glass electrode directly in the respective solution or suspension at 20°C. The mixing time results here from the length of the mixing section, that is to say for example the tube length in m between the mixing point and the reactor, and the throughflow rate of the mixed medium in m³/h at the given cross section of the mixing section (e.g. tube cross section) in m².

Particular preference is given here to a process, characterized in that the homogeneous solution or suspension is produced using an intensive mixer.

Examples of intensive mixers that may be used are T-mixers (cf. Figure 1), Y-mixers, static mixers, jet mixers or circulating pumps, and specifically those which tolerate undissolved solids in particular.

The process is preferably such that the homogeneous solution or suspension formed has a pH of 4.5 to 5.5, preferably of 4.8 to 5.2. Preference is furthermore given here to a process in which the ratio SR_m, normalized to concentration, of circulating rate of the suspension (bulk) to feed rate (alkali metal-Met-Met) reaches a value of 5 to 17, preferably of 7 to 15. In this way it is possible to obtain a comparatively coarse and hence better handleable product having a median of the particle size distribution X50 of about 100 to 350 pm (cf. Figure 3).

Very short mixing times in the range from 500 to 2500 milliseconds have proved to be particularly favourable.

In order to be able to optimally configure this mixing-in, it was shown with the present invention that the momenta of the liquids to be mixed, that is to say alkali metal-Met-Met solution and pH- adjusted Met-Met suspension, must be in the correct ratio. It is unimportant here whether the mixing-in is effected directly in the reactor or via a T-mixer in the circulation line. The latter variant has the advantage that the momentum ratios can be adapted more easily or can be varied in the event of different capacities.

Compared to the publication from H. Rehage et al. (Chemical Engineering Science 207 (2019), 258 ff.), who investigated the precipitation reaction between barium chloride solution and sodium sulfate solution, it has moreover been shown that in the present case the quality of the mixing can be increased further when the streams to be mixed in the T-mixer are supplied to each other from opposite directions (cf. Figure 1) and not, as presented in the publication, metered in at a right angle. In the case of Met-Met, metering in a T-mixer with this right-angled orientation analogously to Rehage does not lead to an adequate crystal quality.

Preference is therefore given to a process which is characterized in that, if a T-mixer or Y-mixer is used, the angle of incident flow at which the two streams meet one another is 120 to 180°, preferably 150 to 180°, especially around 180°.

It is further preferable, in the process according to the invention, for the dilute mineral acid solution used to be aqueous sulfuric, hydrochloric or phosphoric acid solution, preferably aqueous sulfuric acid solution, for example 2N sulfuric acid.

Moreover, the DL/LD-methionylmethionine alkali metal salt used is preferably the sodium salt or potassium salt, especially the sodium salt of DL/LD-methionylmethionine.

The process according to the invention can advantageously be carried out either batchwise or continuously.

Now, using these newly obtained findings (pH regime, quality of mixing in), it is possible to precipitate a readily filterable product, DLLD-Met-Met (AQUAVI®Met-Met), which can be easily washed and dried later on. The tendency towards clumping is significantly reduced by the crystal size and form and the achievable residual moisture contents after the solid/liquid separation. The product which is ready for sale moreover also exhibits a relatively high bulk density and a markedly reduced dust content, which significantly improves the handling properties such as the flowability or the dustiness, for example. It furthermore exhibits high mechanical strength (cf. long-term stirring test in Example 4, Figure 4).

Overall process for preparing readily filterable DLLD-Met-Met particles

A further subject of the present invention is the following overall process (cf. Figure 5) for obtaining diastereomerically pure DL/LD-methionylmethionine, characterized in that a. methionine hydantoin together with alkali metal base is converted to afford a diastereomeric mixture of DL/LD-methionine diketopiperazine and DD/LL-methionine diketopiperazine (DLLD-DKP and DDLL-DKP) b. the DLLD-DKP and DDLL-DKP from a. are brought to crystallization by concentrating or cooling the reaction solution from a. c. the DLLD-DKP and DDLL-DKP crystallized out are separated off from the DKP mother liquor d. the DLLD-DKP and DDLL-DKP separated off are mixed into water and the mixture is brought, by addition of appropriate amounts of MOH (M = alkali metal), to a pH of 10 to 14, preferably 13, 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. the pH of the solution or suspension from d., measured at 20°C, is lowered (acidification), by mixing according to the invention with appropriate amounts of mineral acid as per the process according to the invention described above, to a pH of 4 to 6, preferably to 4.5 to 5.5, particularly preferably to 4.8 to 5.2, f. evaporation of water and/or cooling is/are used to produce a suspension (precipitation) which consists of a solids fraction, which predominantly contains DL/LD-methionylmethionine, and mother liquor, which predominantly contains DD/LL-methionylmethionine, g. the solids fraction from f. is separated off from the mother liquor and h. the solids fraction separated off from g. is alternatively washed and/or dried, with diastereomerically pure DL/LD-methionylmethionine being obtained, and i. the remaining DD/LL-methionylmethionine-containing mother liquor from g. is reacted, by means of cyclization and epimerization, according to the procedure described in parallel application EP20217816.6 (the contents of which are incorporated by reference) (cf. also Claim 1 therein) 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. this is then recycled into step b.

"Diastereomerically pure" and "essentially diastereomerically pure" are understood in this context to mean a product which contains at least 90 mol% of the desired DL/LD diastereomers, preferably at least 95 to 97 mol% based on the total content of methionylmethionine (Met-Met) present.

Description of the Figures:

Figure 1 shows a diagram of a typical T-mixer (a) and Y-mixer (b) *).

In both diagrams A to C have the following meaning:

A: Inlet for component A (acid for acidification)

B: Inlet for component B (basic alkali metal-Met-Met solution)

C: Outlet for component C (neutralized Met-Met solution or suspension)

*) Figure 1 has been taken from the Internet publication "Fallungskristallisation von Katalysatorvorstufen" [Precipitation crystallization of catalyst precursors] of the Institut fur Thermische Verfahrenstechnik (KIT), https://www.tvt.kit.edU//21_3139.php

Figure 2 shows a loop reactor for batchwise and continuous modes.

The figure illustrates the different reactor modes:

Conventional batch:

Feed of the basic alkali metal-Met-Met solution B - via sidestream into reactor (dashed line)

T-mixer batch:

Feed of the basic alkali metal-Met-Met solution B - in batchwise mode via T-mixer in circulation line

T-mixer continuous:

Feed of the basic alkali metal-Met-Met solution B - continuously via T-mixer in circulation line and continuous outflow of the neutralized product solution B

Figure 3 shows the median X₅o of the obtained particle size distribution in continuous and batchwise modes (Examples 1, 2 and 3) as a function of the SR_m value.

Figure 4 shows the particle size distributions before and after stirring for 34 h (Example 4)

Figure 5 shows the scheme for the preparation of DL/LD-methionylmethionine.

The scheme comprises the following steps: a. reaction of methionine hydantoin with alkali metal base to give DLLD/DDLL-Met-DKP b. crystallization of DLLD/DDLL-Met-DKP c. separating-off of DLLD/DDLL-Met-DKP c1 . discharge of DKP mother liquor c2. wastewater treatment d. alkaline hydrolysis of DLLD/DDLL-Met-DKP to DLLD/DDLL-Met-Met e. acidification and f. precipitation of DLLD-Met-Met g. separating-off of the solid DLLD-Met-Met h. washing and/or drying of DLLD-Met-Met hi . bagging of DLLD-Met-Met i. reaction and epimerization of DDLL-Met in DDLL-Met-containing mother liquor to give

DLLD/DDLL-Met-DKP j. recycling of DLLD/DDLL-Met-DKP into step c.

Examples

The examples presented were carried out in an industrial pilot plant.

Definitions and methods

SR (speed ratio) [-] = circulation rate of the suspension in the reactor [cbm/h]/feed rate [cbm/h]

SR_m (speed ratio modified) [1/% by weight] = circulation rate of the suspension in the reactor [cbm/h ]/feed rate [cbm/h*]*NaMetMet concentration [% by weight].

The particle size distribution of the particles in the suspension was determined using a Horiba LA 350 laser scattered light spectrometer in the measurement range from 0.1 to 1000 pm. Determination of bulk density

The bulk density in kg/L was determined using a 1 L measuring cylinder, which was filled with the bulk material exactly 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

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

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

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.

Example 1 (conventional batchwise process for the precipitation of Met-Met particles)

An Na-Met-Met suspension (with 30% by weight of Met-Met), primarily produced in the process for preparing Met-Met as per W02010043558A1 , was circulated in a stirred reactor with loop (as depicted in Figure 2) with a circulation rate of between 35 and 50 cbm/h. The Na-Met-Met solution and the circulation solution admixed with sulfuric acid (addition of dilute sulfuric acid with a pH of 2- 3 into the circulation line) were mixed directly in the stirred reactor which, as mixing and residence vessel, was part of the overall loop reactor. The product mixture formed was not discharged during the reaction in this case, and instead the reactor was operated up to its maximum fill level and then a sample was taken for analysis of the particle size distribution. The results are plotted in Figure 3 in the form of the median values X50 of the particle size distribution. Example 2 (T-mixer in the batchwise process for the precipitation of Met-Met particles)

An Na- Met- Met suspension (with 30% by weight of Met-Met), primarily produced in the process for preparing Met-Met as per W02010043558A1 , was circulated in a stirred reactor with loop (as depicted in Figure 2) with a circulation rate of between 35 and 50 cbm/h. The Na-Met-Met solution and the circulation solution admixed with sulfuric acid (addition of dilute sulfuric acid with a pH of 2- 3 into the circulation line) were mixed via a T-mixer (analogous to Figure 1) above the stirred reactor, the mixture being introduced directly into the stirred reactor from this T-mixer. The product mixture formed was not discharged during the reaction in this case, and instead the reactor was operated up to its maximum fill level and then a sample was taken for analysis of the particle size distribution. The results are plotted in Figure 3 in the form of the median values X50 of the particle size distribution.

Example 3 (T-mixer in the continuous process for the precipitation of Met-Met particles) Example 3 proceeded as in Example 2, however, the product mixture formed was continuously discharged during the reaction so that the fill level in the reactor was kept approximately the same over the duration of the reaction and after approximately one day of operation a sample was correspondingly taken from the continuous discharge stream for analysis of the particle size distribution. The results are plotted in Figure 3 in the form of the median values X50 of the particle size distribution.

Example 4 (mechanical stability of the Met-Met particles)

An aqueous suspension of approximately 15% by weight of DLLD-Met-Met was stirred continuously in an industrial stirred reactor (Figure 2) for 34 h at a stirring speed of 60 rpm without circulation via the heat exchanger. A sample was taken both at the start and at the end of the stirring test and the particle size distribution of the particles in the suspension was determined using a Horiba LA 350 laser scattered light spectrometer in the measurement range from 0.1 to 1000 pm.

Both particle size distributions determined have a maximum above 100 pm and do not exhibit any significant differences, which illustrates the high mechanical stability of the particles according to the invention (Figure 4).

Claims

1 . Process for producing readily filterable particles of DL/LD-methionylmethionine, characterized in that a stream of aqueous solution or suspension containing DL/LD- methionylmethionine alkali metal salt is mixed with a dilute aqueous mineral acid solution so that, within a mixing time of at most 5000 milliseconds, preferably at most 3000 milliseconds, a suspension is formed having a pH of 4 to 6, the pH being measured using a glass electrode directly in the suspension at 20°C.

2. Process according to Claim 1 , characterized in that the suspension is produced using an intensive mixer.

3. Process according to Claim 2, characterized in that the intensive mixer used is a T-mixer, a Y-mixer, a static mixer, a jet mixer or a circulating pump.

4. Process according to any of Claims 1 to 3, characterized in that the suspension formed has a pH of 4.5 to 5.5, preferably of 4.8 to 5.2.

5. Process according to any of Claims 1 to 4, characterized in that the ratio SR_m of circulating rate (bulk) to feed rate (alkali metal-Met-Met) based on the alkali metal-Met-Met concentration reaches a value of 5 to 17, preferably of 7 to 15.

6. Process according to any of Claims 1 to 5, characterized in that the mixing time is in the range from 500 to 2500 milliseconds.

7. Process according to any of Claims 3 to 6, characterized in that, if a T-mixer or Y-mixer is used, the angle of incident flow at which the two streams meet one another is 120 to 180°, preferably 150 to 180°, especially around 180°.

8. Process according to any of Claims 1 to 7, characterized in that the dilute mineral acid solution used is aqueous sulfuric, hydrochloric or phosphoric acid solution, preferably aqueous sulfuric acid solution.

9. Process according to any of Claims 1 to 8, characterized in that the DL/LD- methionylmethionine alkali metal salt used is the sodium salt or potassium salt, preferably the sodium salt of DL/LD-methionylmethionine. Process according to any of Claims 1 to 9, characterized in that the process is carried out batchwise or continuously. Process for obtaining diastereomerically pure DL/LD-methionylmethionine, characterized in that a. methionine hydantoin together with alkali metal base is converted to afford a diastereomeric mixture of DL/LD-methionine diketopiperazine and DD/LL-methionine diketopiperazine (DLLD-DKP and DDLL-DKP) b. the DLLD-DKP and DDLL-DKP from a. are brought to crystallization by concentrating or cooling the reaction solution from a. c. the DLLD-DKP and DDLL-DKP crystallized out are separated off from the DKP mother liquor d. the DLLD-DKP and DDLL-DKP separated off are mixed into water and the mixture is brought, by addition of appropriate amounts of alkali, to a pH of 10 to 14, preferably 13, 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. the pH of the solution or suspension from d., measured at 20°C, is lowered, by mixing with appropriate amounts of mineral acid solution as per at least one of Claims 1 to 10, to a pH of 4 to 6, preferably to 4.5 to 5.5, particularly preferably to 4.8 to 5.2, f. evaporation of water and/or cooling is/are used 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. the solids fraction from f. is separated off from the mother liquor and h. is alternatively washed and/or dried, with diastereomerically pure DLLD- methionylmethionine being obtained, and i. the remaining DD/LL-methionylmethionine-containing mother liquor from g. is converted by cyclization and epimerization 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. this is then recycled into step b.