Cyclic Peptide Cyclization Positioning to Reduce Dimer By-Products
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Solution Overview
Problem
Existing methods for producing cyclic peptide compounds with a double bond crosslinked between amino acids suffer from low selectivity due to the formation of cyclic dimers as by-products, and require excessive reagents and solvents, making them unsuitable for mass production. Additionally, there are no reported examples of crystal forms of these compounds.
Innovation Solution
A method involving liquid phase fragment coupling and specific cyclization positions is employed to reduce cyclic dimer formation, using solvents like acetonitrile and condensation reagents like HATU, resulting in a more efficient production process with reduced by-products. Crystallization is also used to obtain stable crystal forms of the cyclic peptide.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If cyclization is performed at the cyclization position A as described in Patent Literature 1, then the cyclic peptide compound (1) can be produced, but cyclic dimers are formed as by-products and the ratio between the cyclic peptide compound (1) and the cyclic dimer is only 75:25, which is low in selectivity
Solution Approach 1:
The invention changes the cyclization position from position A to position B, which is a parameter change in the reaction conditions. This parameter change leads to significantly reduced cyclic dimer formation and improved selectivity, achieving a ratio of more than 95:5 between the cyclic peptide compound (1) and the cyclic dimer
Solution Approach 2:
The invention introduces a specific protecting group (Fmoc) at the N-terminal amino acid residue before the cyclization reaction. This preliminary protection prevents unwanted reactions at the N-terminal position and directs the cyclization to occur at the desired position B, thereby reducing cyclic dimer formation
2Ease of manufacture
If solid phase synthesis is used to produce the cyclization precursor peptide compound, then the peptide can be synthesized, but excessive amounts of amino acids and reagents and a large amount of organic solvents are required for washing in each step, making it undesirable for mass production
Solution Approach 1:
The invention extracts the peptide synthesis process from the solid phase support and performs it in solution phase. This allows for more efficient reagent utilization and reduces the need for excessive washing steps, thereby reducing waste of amino acids and reagents while maintaining synthesis capability
Solution Approach 2:
The invention changes the synthesis phase from solid phase to solution phase, which is a fundamental parameter change. This change enables better control over reagent consumption and reduces solvent usage, making the process more suitable for mass production
3Productivity
If conventional cyclization methods are used, then the cyclic peptide compound can be produced, but the process is not efficient for mass production due to low selectivity and high by-product formation
Solution Approach 1:
The invention changes multiple parameters simultaneously: the cyclization position from A to B, the protecting group strategy, and the reaction conditions. These parameter changes work together to achieve high selectivity (>95:5 ratio) while maintaining high productivity suitable for mass production
Solution Approach 2:
The invention uses specific protecting groups as intermediaries to control the cyclization reaction. The Fmoc protecting group at the N-terminal position acts as a mediator that directs the reaction to occur at position B while preventing unwanted side reactions, thereby achieving both high selectivity and efficiency
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
The method significantly reduces the amount of cyclic dimers and other by-products, improving selectivity and enabling mass production with reduced solvent use, while providing stable crystal forms of the cyclic peptide.
Implementation Method 1
reacting an N-terminal amino acid residue of a peptide compound represented by formula (2a) or (3a) with a C-terminal amino acid residue of the peptide compound in a solvent for cyclization (cyclization step)
Implementation Method 2
in a solvent for cyclization
Implementation Method 3
Crystallization is also used to obtain stable crystal forms of the cyclic peptide
Data Source
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AI summary
As a cyclization method in the production of a cyclic peptide compound having a double bond crosslinked between amino acids, there is provided a cyclization method by means of a cyclization position that can reduce the amount produced of a cyclic dimer, which is a by-product. There is also provided, as a method for producing a cyclization precursor peptide compound, an efficient production method in which three fragment peptides are each synthesized and liquid phase fragment coupling is performed for synthesis. Furthermore, there are provided a crystal of a cyclic peptide compound and a method for producing the crystal by crystallization.