Solid Phase Oligomeric Conjugation Yield
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Solution Overview
Problem
Existing methods for conjugating oligomeric compounds, particularly those involving phosphoramidite functionalized conjugate groups, face low yields and require multiple purification steps, limiting their effectiveness and efficiency.
Innovation Solution
A solid phase method involving a phosphoramidite functionalized conjugate group is used to conjugate oligomeric compounds, where the group is recirculated and oxidized to form a phosphate or thiophosphate linkage, followed by treatment with ammonia, enhancing yields and simplifying the process by reducing the need for additional purification steps.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing methods for conjugating oligomeric compounds are used, then the conjugation can be performed, but the yield is low and multiple purification steps are required
Solution Approach 1:
The patent extracts the oligomeric compound from the solid support phase into solution phase after conjugation, allowing for simplified purification. The compound is cleaved from the solid support using ammonia treatment, which enables easy separation and purification without requiring multiple complex purification steps, thereby improving both yield and reducing process complexity
Solution Approach 2:
The patent employs parameter changes by optimizing the conjugation conditions including using specific phosphoramidite reagents, controlling reaction time and temperature, and adjusting the concentration of reagents. These parameter optimizations lead to significantly improved conjugation yields while maintaining a simplified single-purification-step process
2Ease of manufacture
If existing conjugation methods are used, then the process can be completed, but it requires multiple purification steps which reduces efficiency
Solution Approach 1:
The patent performs preliminary action by conducting the conjugation reaction on a solid support with pre-attached oligomeric compounds. This solid-phase approach allows for easy washing and purification by simple filtration, eliminating the need for multiple complex purification steps and significantly reducing the time required for the overall process
Solution Approach 2:
The solid support acts as an intermediary that facilitates the conjugation process. It allows the oligomeric compounds to be easily separated from the reaction mixture through filtration, and the ammonia treatment serves as an intermediary reagent that enables clean cleavage and simplifies the purification process, reducing both complexity and time
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 achieves higher yields, typically above 85%, and simplifies the conjugation process by eliminating the need for post-cleavage reactions and multiple purifications, improving the efficiency of oligomeric compound synthesis.
Implementation Method 1
oxidizing the phosphite linkage to a phosphate or thiophosphate linkage
Data Source
AI summary
Provided herein are solid phase methods for the synthesis of conjugated oligomeric compounds and intermediates used in such methods. In particular, the solid phase methods provide for addition of a phosphoramidite functionalized conjugate group to a solid support bound oligomeric compound. The methods also provide an increase in overall yield and a cost benefit over existing methods.