WO2023067061A1 - Précurseurs pour la préparation de dl-méthionine et de dlld-méthionylméthionine - Google Patents

Précurseurs pour la préparation de dl-méthionine et de dlld-méthionylméthionine Download PDF

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Publication number
WO2023067061A1
WO2023067061A1 PCT/EP2022/079209 EP2022079209W WO2023067061A1 WO 2023067061 A1 WO2023067061 A1 WO 2023067061A1 EP 2022079209 W EP2022079209 W EP 2022079209W WO 2023067061 A1 WO2023067061 A1 WO 2023067061A1
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Prior art keywords
methionine
met
dkp
methionylmethionine
mother liquor
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PCT/EP2022/079209
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English (en)
Inventor
Thomas HÄUSSNER
Sascha Braune
Hans-Albrecht Hasseberg
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Evonik Operations Gmbh
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Publication of WO2023067061A1 publication Critical patent/WO2023067061A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

Definitions

  • the present invention relates to methionine derivatives suitable for use in a process for producing methionylmethionine in conjunction with the production of DL-methionine.
  • WO2010043558 A1 discloses a process for producing methionylmethionine (Met- Met), the homologous dipeptide of DL-methionine, which finds increasing use primarily as a high-value methionine source for the feeding of fish and crustaceans kept in aquacultures. Its two stereocentres (two asymmetric carbon atoms) mean that the product is present in the form of two diastereomers, DLLD-Met-Met and DDLL-Met-Met, i.e. in the form of two configurationally isomeric enantiomer pairs, both of which can be utilized by animals particularly readily.
  • WO2010043558 A1 describes various synthetic possibilities for producing Met-Met. However, what all synthetic options have in common is that Met-Met is synthesized via the homologous cyclic dipeptide of methionine, methionine diketopiperazine (I, Met-DKP or DKP).
  • the object underlying the invention was therefore that of providing a process for producing methionylmethionine that minimizes the amount of sulfur-containing starting substances or by- products that after isolation of the DKP needs to be disposed of and is accordingly lost.
  • Byproducts - where unavoidable - should be usefully recycled.
  • the methionine products thus obtained, such as Met-Met or methionine itself, should be produced in high yield and purity and should also have handling and safety properties that are at least as good, but ideally better, than those of the existing product.
  • the stated object is achieved according to the invention by using a suitable process stream from a methionine production facility as starting material for the synthesis of DKP.
  • This process stream contains as the principal component methionine hydantoin formed by the reaction of 3- methylmercaptopropionaldehyde (MMP), carbon dioxide and ammonia.
  • MMP 3- methylmercaptopropionaldehyde
  • Adjustment of the pH with an aqueous potassium-based base to a pH of 8.0-9.0 and heating to temperatures of 170-180°C results in the formation of DKP accompanied by the release of carbon dioxide and ammonia.
  • the extremely low solubility of DKP means that it can be readily separated from the residual secondary components by crystallization, initiated by lowering the temperature.
  • the isolated yield of DKP is in this process step about 30%.
  • BMU bismethionylurea III
  • the present invention thus makes possible a process for the concomitant production of methionine and methionylmethionine that cuts waste volumes to a minimum, thereby conserving the environment and resources to a large degree.
  • the present invention accordingly provides the novel chemical compound of formula II (Hyd-Met) and also a composition comprising Hyd-Met (II) and water and a composition comprising methionine hydantoin, DKP (I), Hyd-Met (II), BMU (III), optionally methionylmethionine and water, which can in each case according to the invention also be used to obtain DKP, Met-Met and also methionine.
  • This composition is obtained by combining the corresponding DKP mother liquor from the Met-Met process with the Met hydantoin solution from the methionine process (cf. Figurel).
  • compositions comprising 0.1 % to 40% by weight of methionine hydantoin, 0.1% to 5% by weight of DKP, 0.1% to 20% by weight of Hyd-Met, 0.1% to (maximum) 2% by weight of BMU, optionally 0.1% to 5% by weight of methionylmethionine and water.
  • the according to the invention useful compositions can be generated in these ratios on account of the throughput volumes specified by production and the concentration ratios required for DKP separation and can be further employed directly in the methionine process without further processing as surprisingly found by the inventors, which represents a major technical, economic and even ecological advantage.
  • the above mentioned compounds II and III can be produced in house by the chemical processes described hereinbelow and subsequently used as starting substance for further conversion into DKP, Met-Met or else methionine.
  • the procedure of choice is however to recycle those process solutions in which these products occur as by-products of the processes mentioned, and to do this such that methionine in particular, but optionally also DKP or Met-Met, is formed therefrom.
  • the invention thus also provides a process for producing the compound of formula II (Hyd-Met), characterized in that methionine hydantoin is reacted in the presence of base, with the release of 1 mol. equiv. (molar equivalent) of NH3 (cf. example 7).
  • Hyd-Met is separating out as an organic layer after acidifying the alkaline DKP mother liquor to pH 1 to 3, preferably pH 2 by addition of mineral acid.
  • the DKP mother liquor has been typically obtained from a filtration step in which DKP is isolated from a DKP containing reaction liquid which has been previously obtained by the reaction of an alkali base, e.g. sodium hydroxide or potassium hydroxide with methionine hydantoin at higher temperature e.g. 195 to 205 °C for a reaction time of typically 1 to 2 hours.
  • an alkali base e.g. sodium hydroxide or potassium hydroxide with methionine hydantoin at higher temperature e.g. 195 to 205 °C for a reaction time of typically 1 to 2 hours.
  • BMU As known from EP1457486 A1 BMU is convertible to DL-methionine. Thus BMU can be used as an alternative starting material or intermediate for the industrial production of DL-methionine.
  • the invention additionally provides a process for producing the compound of formula III (BMU-Met), characterized in that the compound of formula II (Hyd-Met) undergoes alkaline hydrolysis to the alkali metal salt of compound I and that this is converted by reaction with appropriate amounts of mineral acid, preferably hydrochloric acid, sulfuric acid or phosphoric acid, into the free acid of formula (III) (cf. example 10 and Figure 1).
  • the invention further provides, in addition, a process for producing the above mentioned composition, characterized in that 3-methylthiopropionaldehyde is reacted with HCN, NH3 and CO2 in the presence of at least 20% to 80% by weight, preferably with 50% to 70% by weight, of water, based on the total amount of 3-methylthiopropionaldehyde, HCN, NH3, CO2 and water used, at a temperature of 90 to 220°C, preferably at 95 to 150°C, to give an aqueous methionine hydantoin solution and that this is then combined with a DKP mother liquor comprising methionine diketopiperazine, Hyd-Met (II), BMU (III), Met-Met and Met that originates from the separation of DKP in a process for producing Met-Met from DKP (cf. Figure 1).
  • the invention also provides the associated processes for producing Met-Met and methionine, that is to say a process for producing DL-methionine by hydrolysis of a compound of formula II (Hyd- Met) to the alkali metal salt of DL-methionine and subsequent neutralization with acid to methionine.
  • the hydrolysis is preferably carried out at temperatures of 160-180°C and with min. 1 mol. equiv. (preferably 1 - 5 mol. equiv., most preferably 1.2-5 mol. equiv.) of base in order to ensure rapid and/or complete conversion.
  • a further embodiment of the invention is lastly a process for producing DL-methionine by alkaline hydrolysis of the above mentioned composition to the alkali metal salt of methionine and subsequent neutralization with acid to DL-methionine (cf. examples 5 and 6 and Figure 1).
  • the invention also provides a process for producing DL-methionine and methionine diketopiperazine (DKP), characterized in that a DKP-containing mother liquor is concomitantly hydrolysed in the step of alkaline hydrolysis of methionine hydantoin to the alkali metal salt of methionine of a methionine production process, wherein the DKP-containing mother liquor originates from a process for producing DKP starting from a precursor product comprising methionine hydantoin, said process comprising the process steps formation of DKP, crystallization of DKP and separation of DKP from the associated DKP mother liquor.
  • DKP DL-methionine and methionine diketopiperazine
  • the alkali metal salt of methionine initially obtained is then neutralized with acid to methionine.
  • the acid used can for example be carbonic acid, sulfuric acid or hydrochloric acid.
  • the separated DKP undergoes alkaline hydrolysis to the alkali metal salt of Met-Met and this is then neutralized with acid to Met-Met.
  • the invention also provides an overall process for the (concomitant) production of methionylmethionine and DL-methionine, characterized in that (cf. sequence of the steps in the flowchart in Figure 1) a. an aqueous solution comprising methionine hydantoin together with alkali metal base is reacted to form methionine diketopiperazine (DKP, I), b. the DKP from a. is brought to crystallization by concentrating or cooling the reaction solution from a., c. the crystallized DKP from b. is separated from the DKP mother liquor, d. the DKP separated off in c.
  • DKP methionine diketopiperazine
  • aqueous solution or suspension of the alkali metal salt of methionylmethionine e. the pH of the solution or suspension from d., measured using a pH electrode at 20°C, is lowered, by mixing with appropriate amounts of mineral acid solution, to a pH of 4 to 6, preferably to 4.5 to 5.5, more preferably to 4.8 to 5.2, f.
  • evaporation of water and/or cooling is/are used to produce a suspension consisting of a solids fraction that mainly comprises methionylmethionine, and residual amounts of a methionylmethionine-containing mother liquor, g. the solids fraction from f. is separated from the mother liquor and h. this is washed and/or dried, affording (highly pure) methionylmethionine, and i. the methionylmethionine-containing mother liquor from g. undergoes a cyclization reaction giving rise to an aqueous solution or suspension comprising methionine diketopiperazine, which is then recycled to step b., and j. the DKP mother liquor from c.
  • the composition formed in j. is subjected to an alkaline hydrolysis to the alkali metal methioninate, preferably in the corresponding hydrolysis part of a methionine production facility, l. the alkali metal methioninate from k. is neutralized with acid, giving rise to a methionine suspension, m. the methionine from the suspension in I. is isolated, washed and dried.
  • the composition obtained in j. is preferably formed by combining the DKP mother liquor from c. and the methionine hydantoin solution from the methionine process in a weight ratio of from 1 :1 to 1 :1000, preferably from 1 :3 to 1 :100, more preferably from 1 :5 to 1 :20. Stable, continuous operation, and thus the high robustness, of the combination according to the invention of the two subprocesses into the overall process has been demonstrated here, even with long-term operation, and affords the two end products DL-methionine and Met-Met in very good product quality, which is likewise greatly advantageous.
  • the broad scope for variation in the weight ratios of the process solutions to be combined - the DKP mother liquor from c. and the methionine hydantoin solution from the methionine process - means there is also a relatively broad scope for variation in the amounts of DL-methionine and Met-Met that can be concomitantly produced.
  • the surprisingly high flexibility of the overall process of the invention thus makes it possible to vary the amounts of methionine and Met-Met produced according to market demand, which is of high economic value.
  • the aqueous solution comprising methionine hydantoin mentioned in a. can essentially be prepared according to the details for the production of a methionine hydantoin solution provided in EP 780370 A2 in Figure 1.
  • Steps k. to m. correspond to the hydantoin hydrolysis process section described in EP 780370 A2 in Figures 2 + 3, but relating to the methionine hydantoin solution only, and the hydrolysis conditions specified therein can likewise be employed in the overall process claimed here.
  • Figure 1 shows a scheme for the methionine/methionylmethionine process.
  • the scheme comprises the following steps (List of reference numerals):
  • Forming an aqueous solution comprising methionine hydantoin a. reacting to form DKP starting from the preceding methionine hydantoin solution with the aid of an alkali metal hydroxide (MOH), b. crystallizing of the DKP from a., c. separating the crystallized DKP from b. from the DKP mother liquor, d. hydrolysing the separated DKP from c. with the aid of an alkali metal hydroxide (MOH) to the alkali metal methioninate (M-Met-Met), e. acidifying the hydrolysate from d. by addition of acid, with the release of methionylmethionine and f.
  • MOH alkali metal hydroxide
  • composition from j. comprising methionine hydantoin, Hyd-Met, bismethionylurea, DKP and methionylmethionine to form the alkali metal methioninate in the hydrolysis part of a methionine production facility, l. neutralizing the alkali metal methioninate from k. with acid, giving rise to a methionine suspension, m. isolating, washing and drying of the methionine from I., ml . bagging of the methionine.
  • Figure 2 shows a DKP synthesis reactor/hydrolysis reactor, wherein the reference numerals have the meanings stated in the table below.
  • Example 1 Preparation of methionine hydantoin solution according to EP780370 A2 (not part of the invention)
  • methionine hydantoin solution for further use in the examples was prepared from MMP, HCN and ammonia according to EP 780370 A2, examples 1-4, page 9, line 54 to page 10, line 4).
  • example 7 an intermediate methionine hydantoin solution was first of all prepared from MMP, HCN and (NH ⁇ CCh and reacted further for 6 h at 160°C to form DKP and this product obtained in the form of a solid precipitate was filtered off from the DKP mother liquor and the two products provided for further examples. Isolated yield of DKP 64%.
  • Example 3 (comparative): Technical hydantoin solution was reacted with working solution (pH > 12, see below), which corresponds to the operating mode of a pure methionine process without recycling of the DKP mother liquor (cf. Figure 1 , left part of flowchart).
  • Example 4 Exclusively DKP filtrate was reacted with working solution.
  • the working solution here is a strongly alkaline aqueous solution of mainly KHCO3 and K2CO3 having a pH of > 12, which is obtained in the concentration of the mother liquor from the methionine crude crystallization and is, after replenishing lost proportions of hydroxide equivalents in the form of pure KOH, recycled to the methionine process as hydrolysis agent in accordance with EP 780370 A2 example 7.
  • the mixtures in examples 5 and 6 are particularly suitable as an input stream composition for a methionine/Met-Met via DKP production process according to the invention.
  • the reactor was initially charged with the calculated amount of working solution (cf. Table 1) from a corresponding reservoir vessel via pipe conduit 2 and this was heated to min. 160°C. Steam was then introduced and, on reaching steady state, the hydantoin solution or the DKP filtrate or the corresponding mixture of the two was transferred to the reactor from the reservoir and reacted accordingly therein (Tab. 1).
  • composition primarily generated here corresponds to the above aqueous composition (cf. also Figure 1 j.), comprising Met hydantoin, DKP (I), Hyd-Met (II), BMU (III) and proportions of methionylmethionine and DL-methionine already present.
  • Table 1 Overview of the set parameters for examples 4 to 6 with DKP filtrate in a comparison with example 3 without DKP filtrate (corresponding to pure methionine process)
  • the hydrolysis ratio shown in Table 1 was defined beforehand and the respective mass of working solution to be used calculated. Because of the varying concentrations of the solutions used (methionine hydantoin solution and DKP filtrate), the concentrations of the reaction solutions (compositions) for the hydrolysis were likewise of varying strength.
  • Table 2 Chemical compositions of hydrolysed solutions (examples 4-6) in a comparison with methionine process solution (example 3)
  • the aqueous phase was run off and the organic phase extracted again by shaking with 400 mL of lukewarm water. Another 300 mL of water was then added and the mixture treated with 30% KOH solution until the pH had risen to > 9. After shaking, the phases were separated, with the brownish colour now present in the aqueous phase. The organic phase was separated off and the aqueous phase extracted again by shaking with 50 mL of ethyl acetate. After adding a further 300 mL of ethyl acetate, the funnel contents were again adjusted to pH 2 with 20% HCI solution, shaken and the phases separated.
  • the aqueous phase was finally extracted one more time by shaking with 50 mL of ethyl acetate and the organic phases were combined.
  • HPLC analysis approx. 5.7% of Met hydantoin.
  • the combined organic phases were extracted again by shaking with three 400 mL volumes of lukewarm water.
  • HPLC analysis contains 2.4% of hydantoin.
  • the organic phase was diluted with a further 50 mL of ethyl acetate and extracted by shaking with three 400 mL volumes of lukewarm water.
  • the organic phase was then diluted with ethyl acetate to a total volume of about 300 mL and dried over MgSC .
  • the solution was filtered through a silica gel 60 column (200-500 pm, 15 cm, 4 cm diameter) over a period of about 20 min. This resulted in most of the brownish black colour remaining on the silica gel.
  • the light brown, clear solution was evaporated over the weekend under a stream of nitrogen.
  • BMU is obtained as the primary reaction product in the hydrolysis of Hyd-Met.
  • This example examined which reaction products are formed when BMU is broken down hydrolytically.
  • dilute aqueous BMU solutions having a concentration of 0.031 mol.L' 1 were hydrolysed at 100°C in aqueous solutions to which were added varying amounts of KOH and the progress of the reaction monitored by HPLC.
  • the results for the course of the reactions with KOH are shown in Table 4. From this it can be seen that, with 2 mol. equiv. of KOH, a decrease in the BMU content occurs alongside a commensurate increase in the content of Hyd-Met and methionine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne le composé chimique de formule (II), une composition comprenant de la méthionine hydantoïne, DKP (I), Hyd-Met (II), BMU (III), éventuellement de la méthionylméthionine et de l'eau, ainsi que leur utilisation pour la production éventuellement simultanée de méthionylméthionine et de méthionine, ainsi que des procédés de production correspondants.
PCT/EP2022/079209 2021-10-20 2022-10-20 Précurseurs pour la préparation de dl-méthionine et de dlld-méthionylméthionine WO2023067061A1 (fr)

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EP21203735.2 2021-10-20
EP21203735 2021-10-20

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0780370A2 (fr) 1995-12-18 1997-06-25 Degussa Aktiengesellschaft Procédé de préparation de la D,L-méthionine ou leurs sels
EP1457486A1 (fr) 2001-11-29 2004-09-15 Nippon Soda Co., Ltd. Procede de production de methionine
WO2010043558A1 (fr) 2008-10-17 2010-04-22 Evonik Degussa Gmbh Préparation et utilisation de méthionylméthionine en tant qu'additif aux produits d'alimentation animale, pour des poissons et des crustacés

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0780370A2 (fr) 1995-12-18 1997-06-25 Degussa Aktiengesellschaft Procédé de préparation de la D,L-méthionine ou leurs sels
EP1457486A1 (fr) 2001-11-29 2004-09-15 Nippon Soda Co., Ltd. Procede de production de methionine
WO2010043558A1 (fr) 2008-10-17 2010-04-22 Evonik Degussa Gmbh Préparation et utilisation de méthionylméthionine en tant qu'additif aux produits d'alimentation animale, pour des poissons et des crustacés

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