Plecanatide Synthesis via Convergent Fragment Coupling
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Solution Overview
Problem
Current methods for synthesizing Plecanatide, a Guanylate Cyclase-C (GC-C) agonist, face challenges with low yields and high impurities, making them inefficient and time-consuming, particularly in industrial-scale production.
Innovation Solution
A convergent process combining solid phase and solution phase synthesis of peptide fragments, followed by sequential oxidative cyclization and purification, to achieve high yield and purity of Plecanatide, utilizing specific peptide compounds and protection groups to minimize impurities and optimize the synthesis pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional linear phase synthesis methods are used, then the synthesis process is simpler to implement, but the yield is low and purification is time-consuming
Solution Approach 1:
The peptide synthesis is divided into multiple protected fragments (N-terminal fragment with disulfide bridge, C-terminal fragment) that are synthesized separately and then coupled. This segmentation allows parallel synthesis and reduces the complexity of the overall process, improving yield while maintaining manageable purification steps.
Solution Approach 2:
The disulfide bridge formation is performed preliminarily during fragment synthesis while protecting groups are still in place. This preliminary action stabilizes the fragments and simplifies subsequent coupling and purification steps, reducing overall purification time.
2Manufacturing precision
If multiple protection groups and sequential coupling steps are used, then the purity of Plecanatide is improved, but the synthesis process becomes more complex and time-consuming
Solution Approach 1:
The molecule is segmented into fragments with specific protection group patterns. Each fragment is synthesized with predetermined protection groups that simplify coupling. The N-terminal fragment contains Cys(Acm) and Cys(Trt) while the C-terminal fragment contains Cys(Acm), creating a modular system that reduces overall complexity.
Solution Approach 2:
Different protection groups are applied locally to specific cysteine residues based on their position and function. Cys(Acm) is used for intermolecular disulfide bonds while Cys(Trt) is used for intramolecular bonds. This local differentiation optimizes both purity and synthesis efficiency.
3Extent of automation
If solid phase synthesis is used for all fragments, then the synthesis automation is improved, but the scalability for large-scale production is limited
Solution Approach 1:
The synthesis strategy segments fragments into those suitable for solid phase synthesis (smaller fragments like N-terminal and C-terminal pieces) and those better suited for solution phase (larger intermediates). This segmentation enables automation for critical steps while maintaining scalability for bulk production.
Solution Approach 2:
The method changes the phase parameter (solid vs. solution) based on the specific synthesis step and fragment size. Solid phase is used for automated fragment assembly, then solution phase is employed for coupling and disulfide bridge formation, optimizing both automation and scalability.
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 enables the synthesis of Plecanatide with high purity (>98%) and efficient turnaround time, suitable for industrial-scale production, significantly improving yield and reducing impurities compared to existing methods.
Implementation Method 1
oxidising the compound of formula F with charcoal to form disulphide bridge between two Cysteine amino acids at 4th and 12th positions
Implementation Method 2
treating the lyophilized compound of formula G with Iodine to form second disulphide bridge between two cysteine aminoacids at 7th and 15th positions
Data Source
AI summary
The present invention provides a process for the synthesis of Plecanatide, a guanylate cyclase agonist. The process involves convergent synthesis with compounds, i.e., fragment of peptides followed by cyclization. The method provides high yield of Plecanatide with less impurities.