Diastereomerically Pure DL/LD-Methionylmethionine via Epimerization
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Solution Overview
Problem
The existing process for preparing DL/LD-methionylmethionine from DD/LL-methionine results in a product with an unfavorable ratio of diastereomers, leading to differing physical properties such as solubility, flowability, and flammability, which are not suitable for aquaculture applications.
Innovation Solution
A process involving cyclization and epimerization of DD/LL-methionylmethionine to produce DL/LD-2,6-bis(methionyl)-1,4-diketopiperazine, followed by hydrolysis, to achieve a higher proportion of the less soluble DL/LD diastereomer, improving handling and safety properties by converting the more soluble DDLL-Met-Met back into its precursor DKP and epimerizing it to DLLD-Met-Met.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the existing process is used to prepare DL/LD-methionylmethionine from DD/LL-methionine, then the product is obtained, but the ratio of diastereomers is unfavorable (60/40 DLLD/DDLL) leading to high water solubility (21.0 g/l for DDLL) which causes losses through leaching from feed pellets
Solution Approach 1:
The invention changes the diastereomeric composition parameter of the product by introducing an epimerization step that converts DDLL-DKP to DLLD-DKP. This parameter change results in a product with ≥90 mol% DLLD diastereomer, which has low water solubility (0.4 g/l), thereby preventing leaching losses from feed pellets while maintaining animal nutritional requirements
Solution Approach 2:
Instead of directly converting DDLL-Met-Met to DLLD-Met-Met, the invention inverts the approach by first converting both diastereomers to their DKP precursors, then epimerizing the DDLL-DKP to DLLD-DKP before final hydrolysis. This indirect route through the cyclic DKP intermediate enables effective diastereomeric enrichment
2Manufacturing precision
If DDLL-Met-Met crystallizes out in the form of needles, then it can be separated, but it has high water solubility (21.0 g/l) which is unfavorable for aquaculture use
Solution Approach 1:
The invention changes the diastereomeric composition parameter by epimerizing DDLL-DKP to DLLD-DKP during the cyclization process. The resulting product contains ≥90 mol% DLLD diastereomer, which has low water solubility (0.4 g/l), preventing leaching losses while maintaining manufacturability through controlled crystallization
Solution Approach 2:
The invention converts the harmful high solubility of DDLL-Met-Met into a benefit by epimerizing it to DLLD-Met-Met during processing. The low solubility of the DLLD form (0.4 g/l) is then advantageous as it prevents leaching from feed pellets, transforming a previously problematic property into a desirable one
3Loss of substance
If a higher proportion of DLLD-Met-Met is produced, then water solubility decreases (0.4 g/l), but the process requires additional epimerization steps
Solution Approach 1:
The invention merges the cyclization reaction with the epimerization process into a single integrated step. By conducting the cyclization of Met-Met to DKP under conditions that promote epimerization (pH 4-7, elevated temperature), the process simultaneously achieves both objectives without requiring separate epimerization equipment or steps
Solution Approach 2:
The invention maintains continuous useful action by performing epimerization during the cyclization reaction itself rather than as a separate step. The reaction conditions (pH 4-7, temperature) are optimized to continuously promote both cyclization and epimerization, eliminating idle time and additional processing stages
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This process achieves a higher yield of diastereomerically pure DL/LD-methionylmethionine with improved bulk density, flow characteristics, and reduced flammability, making it more suitable for use in aquaculture as an animal feed additive.
Implementation Method 1
a process for the diastereomerically pure preparation of DL/LD-methionylmethionine from DD/LL-methionylmethionine by means of cyclization and epimerization
Implementation Method 2
the undesired DDLL-Met-Met is back-converted into the direct precursor DKP again and in the process is simultaneously epimerized
Implementation Method 3
subsequent hydrolysis
Data Source
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AI summary
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.