Glycoside Amidite Synthesis via Oxidant-Acid Addition Sequence
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Solution Overview
Problem
Existing methods for synthesizing amidite compounds in RNA solid phase synthesis often result in low yield and purity due to the presence of position isomers, which can adversely affect the final product.
Innovation Solution
A process involving the reaction of a glycoside compound with an ether compound in the presence of an oxidizing agent followed by an acid, specifically using N-iodosuccinimide and trifluoromethanesulfonic acid, to suppress the formation of impurity materials with the same molecular weight, thereby achieving high purity amidite compounds.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If an acid such as trifluoromethanesulfonic acid or silver trifluoromethanesulfonate is added to the reaction system followed by an oxidizing agent such as N-iodosuccinimide or N-bromosuccinimide, then the glycoside compound can be synthesized, but impurity materials having the same molecular weight as the desired compound are formed
Solution Approach 1:
The patent inverts the conventional addition sequence by adding the oxidizing agent (N-iodosuccinimide) first to form an intermediate, then adding the acid (trifluoromethanesulfonic acid or silver trifluoromethanesulfonate) subsequently. This reversal of the traditional acid-first approach prevents the formation of position isomer impurities that have the same molecular weight as the desired compound, thereby achieving high purity amidite compounds.
Solution Approach 2:
The oxidizing agent is added in advance to create a reactive intermediate species before the acid is introduced. This preliminary oxidation step modifies the reaction pathway to favor the formation of the desired glycoside compound while suppressing the formation of position isomer impurities, ensuring high purity in the final amidite product.
2Productivity
If conventional protecting groups (TBDMS, TOM, ACE) are used at the 2′ position of amidite, then the synthesis can proceed, but the yield and purity of the obtainable amidite are insufficient
Solution Approach 1:
The patent changes the reaction parameters by using a specific combination of oxidizing agent (N-iodosuccinimide) and acid (trifluoromethanesulfonic acid or silver trifluoromethanesulfonate) in a reversed addition sequence. This parameter change optimizes both the yield and purity of the amidite compound, overcoming the limitations of conventional protecting groups like TBDMS, TOM, and ACE that fail to provide sufficient yield and purity.
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 process effectively suppresses the formation of impurities, allowing for the synthesis of amidite compounds with high purity, as demonstrated by mass analysis and LC-MS results.
Implementation Method 1
the oxidizing agent is selected from the group consisting of N-halogenated succinimide and N-halogenated hydantoin
Implementation Method 2
the acid is selected from the group consisting of perfluoroalkylcarboxylic acid and salts thereof, alkylsulfonic acid and salts thereof, aryl sulfonic acid and salts thereof, perfluoroalkylsulfonic acid and salts thereof
Data Source
AI summary
A process for preparing a glycoside compound represented by formula (3), which includes reacting a glycoside compound represented by formula (1) with an ether compound represented by formula (2) in the presence of an oxidizing agent and an acid to prepare a glycoside compound represented by formula (3),where the oxidizing agent is added to a reaction system, followed by adding an acid thereto,where Ba represents a cytosine group which may be optionally substituted with acyl group, or an uracil group, R1 represents a C1 to C6 alkyl group or a phenyl group, and n is 0 or 1, where an oxidizing agent is selected from N-halogenated succinimide and N-halogenated hydantoin, and an acid is selected from perfluoroalkylcarboxylic acid, alkylsulfonic acid, arylsulfonic acid, periluoroalkylsulfonic acid, and salts thereof, and any combinations thereof, which can provide a synthesis of a desired compound with high purity.