Oligonucleotide Condensation Using Activated Phosphoramidite Coupling
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Solution Overview
Problem
Existing methods for producing oligonucleic acid compounds face challenges in achieving efficient and rapid condensation reactions due to steric hindrance and solvent limitations, leading to prolonged preparation times.
Innovation Solution
A novel method involving a condensation reaction that forms a trivalent phosphorous bond between compounds [A] and [B], characterized by specific structural formulas, to efficiently connect nucleoside units in oligonucleic acid compounds.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If solid-phase method is used for oligonucleic acid synthesis, then the reaction can be performed on supported substrate, but the condensation reaction efficiency decreases due to steric hindrance from the solid-phase carrier
Solution Approach 1:
The invention changes the chemical parameters of the condensation reaction by using phosphoramidite reagents with activated leaving groups (such as chloroamidine, isothiocyanatobenzene derivatives) that enable efficient phosphite triester formation even in the sterically hindered solid-phase environment, thereby maintaining high reaction efficiency while using supported substrates
Solution Approach 2:
The invention introduces an intermediary phosphoramidite reagent structure that mediates between the solid-phase carrier and the nucleoside substrate, where the activated leaving group in the phosphoramidite acts as a reactive intermediary that facilitates bond formation despite steric hindrance from the solid-phase support
2Ease of manufacture
If polystyrene resin is used as solid-phase carrier, then the carrier can be swollen by reaction solvent, but the swelling degree is insufficient in polar solvents like acetonitrile, reducing reaction efficiency
Solution Approach 1:
The invention changes the reaction solvent parameters by employing acetonitrile-based polar solvents combined with activated phosphoramidite reagents, which maintain adequate resin swelling while enabling high reaction rates through the enhanced reactivity of the activated phosphoramidite species that compensates for limited solvent penetration
3Productivity
If liquid-phase method is used for oligonucleic acid synthesis, then the reaction efficiency increases, but column purification is required to remove reaction reagents and solvents
Solution Approach 1:
The invention extracts the purification step from the synthesis process by using solid-phase supported reagents and reactants that can be easily removed by filtration, allowing liquid-phase like reaction efficiency while eliminating the need for column purification to remove reagents and solvents
4Ease of operation
If non-polar solvent such as chloroform is used in condensation reaction, then homogeneous reaction can be achieved, but the reaction requires very long time
Solution Approach 1:
The invention changes the reaction parameters by using polar aprotic solvents like acetonitrile combined with activated phosphoramidite reagents, which provide both homogeneous reaction conditions and significantly accelerated reaction rates through enhanced electrophilicity of the phosphorus center and better solvation of transition states
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 significantly shortens the preparation time of oligonucleic acid compounds by enhancing the reaction efficiency and rate of phosphorous bond formation.
Implementation Method 1
a condensation reaction for forming a bond between a phosphorus atom and an oxygen atom or nitrogen atom deprotected to be enabled to react
Implementation Method 2
During the reaction, the polystyrene resin swells due to the reaction solvent used, and its volume becomes larger than that in a dry state
Data Source
AI summary
The present invention relates to a method for producing a compound represented by general formula [C-1-1], which comprises: a step for reacting a compound represented by general formula [B-1-1] with a compound represented by general formula [P] to form a compound represented by general formula [B-1-2]; and a step for reacting the compound represented by general formula [B-1-2] with a compound represented by general formula [A-1] to form the compound represented by general formula [C-1-1].