Tetrapeptide Crystallization for Industrial SS-31 Production

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Solution Overview

Problem

Current methods for producing SS-31 peptide are not suited for industrial-scale synthesis due to limitations in solid-phase synthesis and purification by preparative liquid-phase chromatography, which are inefficient and difficult to scale up for high-purity production.

Innovation Solution

A novel tetrapeptide compound is synthesized through dehydrocondensation and Boc deprotection steps, followed by catalytic reduction to produce SS-31, utilizing continuous liquid-phase synthesis and further purification by crystallization to achieve high purity on an industrial scale.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If solid-phase synthesis and preparative liquid-phase chromatography are used to produce SS-31, then high purity can be achieved, but the method is not suited for industrial scale production

Engineering Contradiction:
ImprovepurityVSAvoidscalability
Core Design Contradiction:
Manufacturing precisionVSProductivity

Solution Approach 1:

The patent changes the chemical parameters of the intermediate compound by introducing specific protecting groups (Boc, Cbz, Z groups) and modifying the amino acid structure (D-Arg with intramolecular Z(2)2 configuration). These parameter changes enable the compound to crystallize from organic solvents, transforming it from an amorphous substance requiring chromatography into a crystalline substance that can be purified by filtration and washing, thus enabling industrial-scale production while maintaining high purity

Inventive Principle:
Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transition from amorphous to crystalline state of the tetrapeptide intermediate. By designing the molecule with specific protecting groups and structural features, the compound forms well-defined crystals that can be separated by filtration and purified by washing with organic solvents. This phase transition approach replaces the need for preparative liquid-phase chromatography and enables scalable industrial production

Inventive Principle:
Principle #36Phase transitions

2Manufacturing precision

If silica gel column chromatography is used to purify peptides with intramolecular Arg(Z)2, then purity can be improved, but the process complexity and time increase

Engineering Contradiction:
ImprovepurityVSAvoidpurification time
Core Design Contradiction:
Manufacturing precisionVSLoss of time

Solution Approach 1:

The patent exploits the crystallization behavior of the tetrapeptide intermediate from organic solvents to achieve purification. The compound forms crystalline precipitates that can be filtered and washed, providing a rapid purification method that replaces time-consuming silica gel column chromatography. This phase transition approach reduces purification time significantly while maintaining high purity

Inventive Principle:
Principle #36Phase transitions

Solution Approach 2:

The patent employs simple, inexpensive organic solvents (such as ethyl acetate, hexane, or their mixures) for crystallization and purification instead of expensive silica gel and complex chromatography systems. The solvent-based crystallization method is disposable and straightforward, requiring minimal equipment and time, thus eliminating the need for expensive and time-consuming column chromatography

Inventive Principle:
Principle #27Cheap short-living objects (Disposable)

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 method enables the efficient and simple production of high-purity SS-31 on an industrial scale, overcoming the limitations of previous methods by improving purity and scalability through crystallization and catalytic reduction.

Implementation Method 1

catalytic reduction to produce SS-31

Methodology Applied
Scientific EffectCatalytic reduction: Catalysis

Implementation Method 2

catalytic reduction to produce SS-31

Methodology Applied
Scientific EffectReduction: Reduction

Implementation Method 3

improving purity by further crystallization of the novel tetrapeptide compound

Methodology Applied
Scientific EffectCrystallization: Crystallisation

Data Source

PatentEP3060573B1Tetrapeptide compound and method for producing same
Publication Date: 2019.07.17 KANEKA CORP
  • EP3060573B1 patent drawingFigure 1
  • EP3060573B1 patent drawingFigure 2
  • EP3060573B1 patent drawing

AI summary

The present invention is to provide a method for the efficient production on an industrial scale of SS-31 (D-Arg-Dmt-Lys-Phe-NH2), which is an SS peptide. According to the present invention, the desired SS-31 is produced by efficiently synthesizing a tetrapeptide compound as a precursor of SS-31 and improving the tetrapeptide purity by crystallization.