Phosphate-Activated Nucleotide Synthesis for Polyphosphorylated Nucleosides
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Solution Overview
Problem
Existing methods for producing polyphosphorylated nucleosides are inefficient, require expensive starting materials, and involve multiple steps with low yield and poor time and cost performance due to the use of nucleoside 5'-diphosphate and condensing or activating agents.
Innovation Solution
A method for synthesizing polyphosphorylated nucleosides using phosphate-activated nucleotides, involving the reaction of pyrophosphoryl chloride with a co-catalyst compound to prepare a phosphate-activated compound, which is then reacted with a nucleoside to form a 5'-diphosphate-activated nucleotide, followed by condensation with a nucleoside phosphate in water, using catalysts like imidazole and Lewis acids.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleoside 5'-diphosphate is used as starting material and condensing/activating agents are employed, then polyphosphorylated nucleosides can be synthesized, but the production process becomes complex with multiple steps and low yield
Solution Approach 1:
The patent extracts and eliminates the need for expensive nucleoside 5'-diphosphate starting materials and separate condensing/activating agents by incorporating these functions into a single phosphate-activated nucleotide compound. This reduces the number of steps and materials required while maintaining synthesis reliability.
Solution Approach 2:
The patent merges the functions of starting material, activating agent, and reaction substrate into a single phosphate-activated nucleotide compound. This integrated approach consolidates multiple separate steps into one streamlined reaction, reducing process complexity while preserving product yield.
2Productivity
If multiple steps with condensing agents and activating agents are used, then polyphosphorylated nucleosides can be produced, but the production time increases and time efficiency deteriorates
Solution Approach 1:
The patent performs preliminary activation of the phosphate group in the nucleotide compound before the coupling reaction. This pre-activation step eliminates the need for separate condensing and activating steps during the synthesis process, significantly reducing production time while maintaining high productivity.
Solution Approach 2:
The patent ensures continuous useful action by using a phosphate-activated nucleotide that is ready for immediate coupling reaction. This eliminates idle time between steps and maintains continuous progress toward the final product, improving time efficiency without sacrificing production efficiency.
3Reliability
If nucleoside 5'-diphosphate and multiple reagents are used, then polyphosphorylated nucleosides can be synthesized, but the production cost increases
Solution Approach 1:
The patent replaces expensive nucleoside 5'-diphosphate starting materials with more cost-effective nucleoside 5'-monophosphate or nucleoside derivatives that are activated in situ. This substitution reduces raw material costs while maintaining adequate product yield through the phosphate-activated mechanism.
Solution Approach 2:
The patent eliminates the need to purchase and dispose of multiple separate reagents (condensing agents, activating agents, and expensive starting materials) by using a single phosphate-activated nucleotide compound. This reduces both material costs and waste generation, improving cost performance while preserving product yield.
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 efficient production of polyphosphorylated nucleosides using less expensive raw materials with a simplified process, reducing environmental impact and improving yield and time efficiency.
Implementation Method 1
reacting pyrophosphoryl chloride with a co-catalyst compound in a solvent, in the presence or absence of a catalyst compound to prepare a phosphate-activated compound
Implementation Method 2
reacting the phosphate-activated compound obtained in step (a) with a nucleoside in which a base moiety is protected by a protecting group or unprotected to prepare a 5'-diphosphate-activated nucleotide
Implementation Method 3
condensing the 5'-diphosphate-activated nucleotide according to the third to fifth aspects with a nucleoside 5'-phosphate in the presence of water to obtain a polyphosphorylated nucleoside
Implementation Method 4
using catalysts like imidazole and Lewis acids
Data Source
Figure 1(a)~1(b)
Figure 2
Figure 3
AI summary
The present invention provides a polyphosphorylated nucleoside having a structure of formula (I), a phosphate-activated nucleotide used for synthesizing the same and a method for synthesizing the same, and a method for synthesizing a polyphosphorylated nucleoside using the phosphate-activated nucleotide. In the formula, B is a protected or unprotected natural or artificial nucleoside base; R1, R2, R4, and R5 are each H, an alkyl group, or the like, and R1, R2, R4, and R5 may be the same or different; X and Y are each H, OH, OCH3, or the like; h is an integer of 1 to 3; and p, n, m, and q are each 0 or an integer, and p, n, m, and q are in any order, with (p + n + m + q) being an integer of 0 or more and 5000 or less.