Alkoxyphenyl Derivatives for Oligonucleotide Synthesis
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Solution Overview
Problem
Existing methods for synthesizing oligonucleotides, particularly those of 20 mer or more, face challenges such as the need for large excesses of nucleoside phosphoroamidite compounds and tetrazole-based compounds in solid phase synthesis, and difficulties in scaling up equipment and monitoring reaction progress in liquid phase synthesis.
Innovation Solution
The development of an alkoxyphenyl derivative capable of facilitating the synthesis of oligonucleotides and protected oligonucleotides through a liquid phase synthesis method, allowing for the formation of tagged protected nucleosides and nucleotides that can be easily separated and have their tag moiety selectively removed.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If solid phase synthesis method is used, then oligonucleotide synthesis can be performed, but large excess of nucleoside phosphoroamidite compound and tetrazole-based compound must be used to increase yield
Solution Approach 1:
The patent introduces a solid-supported reagent (tetrazole-based compound on solid support) as an intermediary that enables the reaction to proceed efficiently without requiring large excesses of soluble reagents. The solid support allows for easy separation and reuse, improving both yield and reagent economy.
Solution Approach 2:
The patent modifies the physical state of the tetrazole-based compound from soluble to solid-supported form, changing its solubility parameter. This allows the reaction to be conducted with stoichiometric or near-stoichiometric amounts rather than large excesses, while maintaining high oligonucleotide yield.
2Productivity
If solid phase synthesis method is used, then oligonucleotide synthesis can be performed, but equipment scale-up is limited and reaction progress monitoring is difficult
Solution Approach 1:
The patent segments the synthesis process into discrete steps with a solid-supported intermediate that can be easily manipulated. The solid-supported tetrazole reagent allows each coupling step to be performed and monitored independently, facilitating scale-up and progress monitoring without complex equipment.
Solution Approach 2:
The solid-supported tetrazole compound serves as an intermediary that makes the reaction progress visible and manageable. The solid support allows for simple filtration and visualization of reaction completion, enabling monitoring without sophisticated instrumentation and allowing straightforward scale-up.
3Productivity
If conventional liquid phase synthesis method is used, then oligonucleotide synthesis can be performed, but rapid synthesis of large amount of oligonucleotides with multidegree of polymerization is difficult
Solution Approach 1:
The patent uses a solid-supported tetrazole compound as an intermediary reagent that simplifies the liquid phase synthesis process. The solid support enables easy separation of excess reagents and byproducts through filtration, dramatically reducing purification complexity while allowing rapid synthesis of large amounts of oligonucleotides with various degrees of polymerization.
Solution Approach 2:
The patent changes the physical state of the tetrazole-based reagent to solid-supported form, which fundamentally alters the ease of manufacture by enabling simple filtration-based purification. This parameter change allows rapid synthesis without complex purification operations, even for large-scale production of oligonucleotides with multidegree of polymerization.
4Adaptability or versatility
If pseudo-solid phase protecting group is used, then protected nucleotide synthesis becomes possible, but deprotection takes long time and selective removal is difficult
Solution Approach 1:
The patent employs a solid-supported tetrazole compound that acts as a disposable, single-use reagent for introducing protecting groups. This approach enables rapid deprotection conditions because the solid support does not require prolonged reaction times for removal, and selective deprotection is achieved through the specific chemistry of the solid-supported reagent that can be quickly removed under mild conditions.
Solution Approach 2:
The patent changes the deprotection conditions by using a solid-supported protecting group strategy that allows removal under milder and faster conditions compared to conventional pseudo-solid phase approaches. The solid support enables deprotection to be completed in shorter times and with better selectivity, reducing loss of time while maintaining versatility in protected nucleotide synthesis.
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 enables the rapid and simple synthesis of oligonucleotides and protected oligonucleotides, overcoming previous limitations by allowing for efficient separation and selective removal of the tag moiety under mild conditions, thus improving the versatility and efficiency of oligonucleotide synthesis.
Implementation Method 1
a method for removing a selective alkoxyphenyl derivative moiety of a protected nucleoside or protected nucleotide
Implementation Method 2
using a boron-containing reducing agent
Data Source
AI summary
The present invention relates to an alkoxyphenyl derivative capable of synthesizing an oligonucleotide by a quicker liquid phase synthesis method than in the prior art, a protected nucleoside and a protected nucleotide to which the alkoxyphenyl derivative is bonded, a method for producing an oligonucleotide using the same, and a method for selectively removing the alkoxyphenyl derivative moiety and the like. A compound represented by the general formula (1) or a derivative thereof:(In the formula,R each independently represents an optionally substituted alkyl group having 10 to 40 carbons.m represents an integer between 1 and 5. When m is 2 or more, a plurality of ROs may be the same or different.X represents O, S, NH, or NRN.n represents an integer from 1 to 4.RN represents an optionally substituted alkyl group having 1 to 6 carbons.)