TIPS-Protected Nucleoside Monomers for 3′-RNA Oligonucleotide Synthesis
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Solution Overview
Problem
The chemical synthesis of oligonucleotides comprising at least one nucleoside with a 3′-hydroxyl group is challenging due to the instability of commonly used protecting groups under deprotection conditions, leading to low yields and high impurities.
Innovation Solution
The use of nucleoside phosphoramidite monomers with a triisopropylsilylether (TIPS) protected 3′-hydroxyl group for coupling and subsequent oxidation or sulfurization to form phosphate triester or phosphorothioate intermediates, followed by deprotection to obtain oligonucleotides with improved yields and reduced impurities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If commonly used protecting groups are used in oligonucleotide synthesis, then the synthesis process is routine and straightforward, but the protecting groups become unstable under deprotection conditions leading to low yields and high impurities
Solution Approach 1:
The patent changes the chemical parameter of the protecting group from commonly used groups (like TBS, TMS) to a specific triisopropylsilylether (TIPS) protecting group. This parameter change enables the group to withstand the harsh deprotection conditions (strong base, heat) while maintaining stability during synthesis, thereby resolving the contradiction between ease of synthesis and stability under deprotection conditions.
2Productivity
If commonly used protecting groups are used, then the synthesis procedure is simple, but the yield of modified oligonucleotides is low due to instability
Solution Approach 1:
The patent applies parameter change by selecting a specific protecting group (TIPS) with enhanced chemical stability. This allows the protecting group to survive the deprotection process without decomposing, thereby preventing yield loss and improving the overall productivity of oligonucleotide synthesis.
3Manufacturing precision
If commonly used protecting groups are used, then the synthesis is routine, but impurities increase due to deprotection instability
Solution Approach 1:
The patent changes the chemical parameter of the protecting group to TIPS, which is specifically designed to be stable under deprotection conditions. This prevents unwanted side reactions and decomposition during the process, thereby reducing impurities and improving manufacturing precision.
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 synthesis of oligonucleotides with enhanced yields and purity, particularly for sequences ranging from about 6 to 50 nucleotides, using automated synthesizers and suitable solvents for coupling, oxidation, and deprotection steps.
Implementation Method 1
The coupling forms a phosphite triester intermediate which can be oxidized or sulfurized to form a phosphate triester or phosphorothioate intermediate
Implementation Method 2
The coupling forms a phosphite triester intermediate which can be oxidized or sulfurized to form a phosphate triester or phosphorothioate intermediate
Data Source
AI summary
The disclosure is directed to monomers and methods for synthesizing oligonucleotides comprising at least one nucleoside comprising a 3′-hydroxyl group.