Oligonucleotide Phosphate Bond Condensation with Quaternary Salt Catalysts
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Solution Overview
Problem
Existing methods for producing oligonucleic acid compounds face challenges in achieving efficient and rapid formation of phosphate bonds, leading to prolonged preparation times due to factors such as steric hindrance and solvent limitations in both solid-phase and liquid-phase synthesis methods.
Innovation Solution
A novel method involving a condensation reaction using a reaction accelerator, such as quaternary ammonium salts, to efficiently form phosphate bonds between nucleoside units in the presence of compounds [A] and [B], allowing for the production of oligonucleic acid compounds with improved reaction efficiency and reduced preparation time.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If solid-phase method is used, then substrate can be supported on solid-phase carrier for heterogeneous reaction, but reaction efficiency and reaction rate decrease due to steric hindrance and limited solvent swelling
Solution Approach 1:
The patent introduces a phase transfer catalyst as an intermediary substance that mediates between the solid-phase carrier and the reaction reagents. The catalyst facilitates the transfer of reagents to the solid phase and enhances the condensation reaction rate, thereby improving reaction efficiency while maintaining the advantages of solid-phase synthesis.
Solution Approach 2:
The patent modifies reaction parameters by using specific solvents (acetonitrile, dimethyl carbonate) and adding phase transfer catalysts to change the reaction environment. This allows the polystyrene resin to swell adequately and enables efficient condensation reactions despite the heterogeneous nature of solid-phase synthesis.
2Productivity
If liquid-phase method is used, then reaction efficiency increases and reaction rate becomes faster, but column purification is required to remove reaction reagents and solvents
Solution Approach 1:
The patent uses a phase transfer catalyst as an intermediary that enables the reaction to proceed efficiently in a homogeneous phase while allowing for simpler purification. The catalyst facilitates reagent transfer and reaction without requiring complex column purification steps.
Solution Approach 2:
The patent changes the reaction parameters by selecting specific solvents and catalysts that allow for both high reaction efficiency and simplified purification, eliminating the need for column chromatography while maintaining fast reaction rates.
3Productivity
If non-polar solvent is used in homogeneous reaction, then reaction can be carried out in homogeneous system with high efficiency, but condensation reaction requires very long time
Solution Approach 1:
The patent optimizes reaction parameters by combining specific non-polar solvents with phase transfer catalysts and adjusting temperature conditions. This combination enables fast condensation reactions in homogeneous systems without requiring very long reaction times.
Solution Approach 2:
The patent creates a composite reaction system combining non-polar solvent, phase transfer catalyst, and heated conditions to achieve both homogeneous reaction conditions and rapid reaction rates, overcoming the limitation of slow condensation in non-polar solvents.
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 method significantly shortens the preparation time of oligonucleic acid compounds by enhancing the reaction efficiency and rate of phosphate bond formation, overcoming limitations of previous synthesis methods.
Implementation Method 1
a method for producing a compound (C) by subjecting a compound (A) having a hydroxyl group or a primary or secondary amino group and a compound (B) having a substituent group containing phosphorous atom to a condensation reaction in the presence of at least one reaction accelerator selected from the group consisting of a quaternary ammonium salt
Data Source
AI summary
The present invention relates to a method for producing a compound [C] of the general formula [C] by subjecting a compound [A] having a hydroxyl group or a primary or secondary amino group and a compound [B] having a phosphorous atom-containing substituent group of the general formula [1] to a condensation reaction, characterized in that the method is carried out in the presence of at least one reaction accelerator selected from the group consisting of a quaternary ammonium salt, a quaternary imidazolium salt, a quaternary morpholinium salt, a quaternary phosphonium salt, a quaternary piperidinium salt, a quaternary pyridinium salt, a quaternary pyrrolidinium salt and a quaternary sulfonium salt.