Pseudo Solid-Phase Protecting Group for Scalable Oligonucleotide Synthesis
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Solution Overview
Problem
The existing solid-phase synthesis processes for oligonucleotides face challenges in scalability due to excessive reagent consumption and difficulty in monitoring reaction progress, and there is a need for cost-effective pseudo solid phase protecting groups that prevent premature cleavage and allow complete cleavage under suitable conditions.
Innovation Solution
The development of a pseudo solid phase protecting group represented by formula II, which is suitable for oligonucleotide synthesis, allowing for simple and efficient production, and can be cleaved under specific conditions, such as treatment with a base.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If solid-phase synthesis is used for oligonucleotide production, then synthesis speed is improved, but reagent consumption increases excessively
Solution Approach 1:
The patent introduces a soluble support as an intermediary carrier that temporarily holds the growing oligonucleotide chain during synthesis. This mediator enables the use of solution-phase chemistry with conventional reagents while maintaining the efficiency of iterative coupling cycles, thereby achieving high synthesis speed without the excessive reagent consumption associated with traditional solid-phase synthesis
2Extent of automation
If solid-phase synthesis is used for oligonucleotide production, then synthesis automation is improved, but real-time reaction monitoring becomes difficult
Solution Approach 1:
The soluble support acts as a soluble intermediary that allows the oligonucleotide chain to be carried in solution throughout the synthesis process. This enables real-time monitoring of reaction progress through standard analytical techniques such as HPLC and NMR, while still allowing the synthesis to be automated through iterative coupling cycles
Solution Approach 2:
The patent enables feedback mechanisms by allowing real-time analysis of intermediate structures and reaction progress through the soluble support system. This feedback information can be used to monitor synthesis quality and adjust conditions, while the process remains automatable through programmed iterative cycles
3Ease of manufacture
If existing pseudo solid phase protecting groups are used, then cleavage is enabled under suitable conditions, but premature cleavage may occur
Solution Approach 1:
The patent applies local quality by designing a protecting group with specific chemical properties that are sensitive to particular conditions. The protecting group is engineered to remain stable during standard synthesis conditions but undergoes controlled cleavage only when specific deprotection conditions are applied, thereby preventing premature cleavage while enabling complete cleavage when needed
Solution Approach 2:
The patent utilizes parameter changes by designing a protecting group that responds to specific changes in reaction conditions. The protecting group maintains stability under normal synthesis parameters (temperature, pH, reagents) but undergoes controlled transformation when specific deprotection parameters are applied, ensuring reliable cleavage control without premature release
4Ease of manufacture
If scalable synthesis methods are developed, then production cost is reduced, but reagent consumption must be controlled
Solution Approach 1:
The soluble support serves as a scalable intermediary that enables the use of conventional solution-phase reagents in a controlled manner. This approach allows for scalable production while maintaining better reagent utilization efficiency compared to traditional solid-phase synthesis, as reagents are consumed only when needed for coupling reactions rather than being excessively consumed throughout the entire synthesis process
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 new protecting group facilitates scalable and cost-effective oligonucleotide synthesis by preventing premature cleavage and enabling complete cleavage, improving reaction monitoring and reducing reagent consumption.
Implementation Method 1
a pseudo solid phase protecting group for protecting a nucleoside, a nucleotide, an oligonucleotide, or a conjugate of a nucleoside, a nucleotide or an oligonucleotide
Implementation Method 2
be amenable to complete cleavage under suitable conditions. Such suitable conditions may comprise treatment with a base
Data Source
Figure 1
Figure 2(a)~2(e)
Figure 3(a)~3(j)
AI summary
A novel pseudo solid phase protecting group and methods for the synthesis of oligonucleotides and oligonucleotide conjugates are provided. The pseudo solid phase protecting group is represented by formula II wherein: * indicates the point of attachment to an oxygen atom of a hydroxyl moiety of the nucleoside, the nucleotide, the oligonucleotide, or of the conjugate of a nucleoside, a nucleotide or an oligonucleotide to be protected; c is 0 or 1; a is an integer of 1 to 12; R3 is H; R5 is O-R6 or H, where R6 is a C8-C40 aliphatic hydrocarbon group; each of R4 is independently O-R6, where R6 is at each occurrence independently a C8-C40 aliphatic hydrocarbon group; b is 1 to 3; with the proviso that if b is 1, at least one of R3 and R5 is not H; and with the further proviso that the sum of all carbon atoms contained in the R3, R4, and R5 moieties present is larger than 23 and smaller than 200.