Oligonucleotide Synthesis Using Amide Extraction Solvents
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Solution Overview
Problem
Existing liquid-phase oligonucleotide synthesis methods face challenges in reducing the number of solid-liquid separation steps, particularly precipitation and filtration, which are tedious and inefficient, especially when using pseudo solid-phase protecting groups, and often require halogenated solvents that are environmentally and economically undesirable.
Innovation Solution
A method involving one-pot synthesis with aqueous extractions using amide solvents containing specific alkyl groups to facilitate the separation of oligonucleotides covalently bonded to a pseudo solid-phase protecting group, minimizing the need for solid-liquid separations and reducing halogenated solvent use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If liquid-phase synthesis with pseudo solid-phase protecting groups is used, then oligonucleotides remain soluble in organic solvents, but multiple solid-liquid separation steps are required which are tedious and inefficient
Solution Approach 1:
The patent changes the solvent parameter from traditional halogenated solvents to amide solvents (DMF, DMA, NMP) to achieve both solubility of oligonucleotides with pseudo solid-phase protecting groups and elimination of solid-liquid separation steps. This parameter change in solvent type resolves the contradiction by maintaining synthetic efficiency while eliminating time-consuming filtration and precipitation steps.
2Productivity
If halogenated solvents are used for liquid-phase synthesis, then oligonucleotide solubility is improved, but environmental and economic sustainability deteriorates
Solution Approach 1:
The patent applies parameter change by substituting halogenated solvents with amide solvents (DMF, DMA, NMP) that have comparable or superior solubilizing properties for oligonucleotides with pseudo solid-phase protecting groups. This replacement eliminates the environmental harm associated with halogenated solvents while maintaining or improving oligonucleotide solubility and reaction efficiency.
Solution Approach 2:
The patent employs readily available, inexpensive amide solvents that can be easily removed and replaced, serving as sustainable alternatives to expensive and environmentally problematic halogenated solvents. These amide solvents achieve the same functional purpose without the harmful environmental footprint.
3Productivity
If solid-phase synthesis is used, then automation and speed are improved, but reagent consumption and difficulty of upscaling worsen
Solution Approach 1:
The patent segments the synthesis approach by using soluble supports (pseudo solid-phase protecting groups) that allow the oligonucleotide to remain in solution rather than being bound to insoluble beads. This segmentation enables the reaction mixture to be handled as a homogeneous solution, dramatically reducing reagent consumption while maintaining synthetic speed and enabling easy upscaling.
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 allows for efficient synthesis of oligonucleotides with minimal solid-liquid separations and minimal halogenated solvent use, enhancing industrial scalability and environmental sustainability.
Implementation Method 1
subjecting a solution comprising the component (C-0)' to one or more liquid-liquid extractions, wherein the organic phase comprises the component (C-0)'
Data Source
Figure 1
AI summary
The invention pertains to methods for the synthesis of oligonucleotides using pseudo solid-phase protecting groups, wherein said method comprises at least one aqueous extraction carried out in the presence of one or more amide solvents SA, wherein each amide solvent SA is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−24 carbon atoms. The invention further pertains to compositions comprising an oligonucleotide which is covalently bonded to a pseudo solid-phase protecting group and a mixed solvent comprising on or more of the aforementioned amide solvents SA.