Method for producing production intermediate, production intermediate thereof, and method for producing crosslinked artificial nucleic acid intermediate by using same
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Solution Overview
Problem
Conventional methods for producing crosslinked artificial nucleic acid intermediates, such as ALNA[Ms], ALNA[mU], ALNA[ipU], ALNA[oxz], ALNA[Trz], and GuNA, pose safety risks due to the use of metal azides and have low yield, making them unsuitable for industrial-scale production.
Innovation Solution
A method involving reductive amination reactions using sodium bis(2-methoxyethoxy)aluminum hydride and crystallization steps to produce these intermediates safely and in high yield, without using hazardous azides, and incorporating novel production intermediates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If metal azide is used as a reagent to introduce a nitrogen atom into a crosslinked structure, then the nitrogen introduction step can be completed, but safety risks such as explosiveness and toxic gas generation occur
Solution Approach 1:
The patent removes the hazardous metal azide reagent from the synthesis pathway entirely. Instead of using metal azide to introduce the nitrogen atom, the invention employs a different chemical approach that achieves the same structural modification without requiring azide compounds, thereby eliminating the safety risks associated with explosiveness and toxic gas generation.
Solution Approach 2:
The patent transforms the problematic azide-based approach into a safe alternative by using a multi-step synthesis route that introduces the nitrogen atom through non-azide intermediates. This conversion maintains the desired chemical transformation while eliminating the harmful properties of metal azide, turning a dangerous process into a safe industrial method.
2Reliability
If a production method without azide compound is used to improve safety, then safety risks are reduced, but the yield of the nitrogen introduction step becomes significantly low
Solution Approach 1:
The patent divides the nitrogen introduction process into multiple sequential steps rather than attempting a single-step transformation. The synthesis pathway is segmented into distinct stages with isolated intermediates, allowing each step to proceed with high yield while maintaining safety. This multi-step approach replaces the low-yield single-step azide-free method with a series of optimized reactions.
Solution Approach 2:
The patent performs preparatory chemical transformations before the final nitrogen incorporation step. By pre-installing appropriate functional groups and preparing reactive intermediates in advance, the methodology enables efficient nitrogen introduction in subsequent steps without requiring hazardous azide compounds, thereby achieving both high safety and high yield.
3Ease of manufacture
If conventional methods are used for industrial production, then existing processes can be maintained, but safety risks and low yield make them unsuitable for large-scale production
Solution Approach 1:
The patent fundamentally changes the chemical parameters of the synthesis process by replacing metal azide with alternative reagents and conditions. This parameter change includes using different chemical species, reaction conditions, and mechanistic pathways that are inherently safer and more efficient, making the process suitable for industrial-scale production while improving both safety and yield.
Solution Approach 2:
The patent introduces safe intermediate compounds that serve as mediators in the nitrogen introduction process. These intermediate structures allow the transformation to proceed through controlled, high-yield steps without direct use of hazardous azide compounds, enabling industrial production with improved safety and efficiency profiles.
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 enables the production of high-quality crosslinked artificial nucleic acid intermediates with good reproducibility and high yield, suitable for industrial applications.
Implementation Method 1
a step of obtaining a compound of formula (III) by subjecting a compound of formula (II) to a reduction reaction with a reducing agent
Implementation Method 2
it has become clear that a production intermediate in the production of crosslinked artificial nucleic acid intermediates can be crystallized
Data Source
Figure 1
AI summary
The present invention is intended to provide a method for producing a production intermediate that is advantageous and safe for industrial production, a production intermediate thereof, and a method for producing a crosslinked artificial nucleic acid intermediate using them. The present invention includes a method for producing a compound represented by Formula (IV): [wherein the symbols are as defined in the specification] from a compound represented by Formula (I): [wherein the symbols are as defined in the specification].