Protected Nucleic Acid Synthesis for Scalable Liquid-Phase Oligomers
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Solution Overview
Problem
Existing methods for synthesizing oligonucleotides face challenges in scalability, reagent usage, and difficulty in monitoring reaction progress, particularly in solid-phase synthesis, while liquid-phase methods are cumbersome and yield low.
Innovation Solution
A method involving the use of a nucleic acid compound with specific structural protections at the 3- or 5-position of the ribose structure, utilizing a liquid phase synthesis that includes deprotection, phosphoramidation, and conversion of phosphite triester bonds to phosphate or thiophosphate bonds, followed by precipitation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If solid-phase synthesis is used, then synthesis speed is improved and automation is enhanced, but scalability is restricted and reaction monitoring becomes difficult
Solution Approach 1:
The patent divides the synthesis process into discrete cyclic steps (activation, coupling, capping, deprotection) that can be performed in a liquid phase, allowing each step to be monitored and controlled independently while maintaining overall synthesis efficiency and enabling scale-up flexibility
Solution Approach 2:
The patent changes the phase parameter from solid-supported to liquid-phase synthesis, fundamentally altering the reaction environment to enable better scalability, reaction monitoring, and intermediate purification while maintaining synthesis speed through optimized liquid-phase reaction conditions
2Ease of manufacture
If liquid phase method is used, then reactivity is improved and intermediate purification becomes possible, but operation complexity increases and yield decreases
Solution Approach 1:
The patent extracts and removes side products and residual reagents through selective precipitation and filtration steps, simplifying the purification process while maintaining high reactivity in the liquid phase synthesis
Solution Approach 2:
The patent discards unwanted side products through selective precipitation and filtration, while recovering and reusing solvents and reagents where possible, reducing operation complexity and improving overall efficiency
3Manufacturing precision
If liquid phase method is used, then intermediate purification becomes possible, but synthesis yield becomes low
Solution Approach 1:
The patent performs preliminary deprotection and activation steps before the main coupling reaction, ensuring that intermediates are in the optimal state for reaction, which maintains high yield while enabling purification between steps
Solution Approach 2:
The patent uses carefully selected solvents and protecting groups as intermediaries that facilitate both purification and high-yield synthesis, allowing intermediate isolation without significant product loss
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 approach enhances yield and simplifies the synthesis process, enabling efficient production of nucleic acid compounds with improved scalability and reaction monitoring.
Implementation Method 1
reacting the nucleic acid compound obtained in the step B with an oxidizing agent or a sulfurizing agent to convert the phosphite triester bond of the nucleic acid compound into a phosphate triester bond or a thiophosphate triester bond
Data Source
AI summary
There are provided a method of producing a nucleic acid compound, in which a nucleic acid compound in which any one of a 3-position or a 5-position of a ribose structure is protected by a structure represented by Formula (1), and the nucleic acid compound. In Formula (1), a ring A represents a condensed polycyclic aromatic hydrocarbon ring or an aromatic heterocyclic ring, YA's each independently represent —OCR2—, —NRCR2—, or —SCR2—, R's each independently represent a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, k represents an integer of 1 to 5, RA's are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one aliphatic hydrocarbon group in k pieces of RA's has 12 or more carbon atoms, and the ring A may further have a substituent in addition to YA and RA.