C-Nucleoside Synthesis Using Bis-Silicon Protection for Scale-Up
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Solution Overview
Problem
The existing synthesis methods for remdesivir's chiral intermediate C-nucleoside compound suffer from low yield, high production cost, and cumbersome operations, limiting its clinical application and scale-up potential.
Innovation Solution
A method involving the use of a secondary amine and a metal lithium reagent with 1,2-bis(chlorodimethylsilyl)ethane to react with a compound represented by Formula 1, allowing for a bis-silicon protection and lithium-halogen exchange, followed by an addition reaction with D-ribonolactone to produce the C-nucleoside compound.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the metal-halogen exchange reaction is performed with TMSCl and n-BuLi to protect the amino group, then the addition reaction can proceed, but the yield is low (25%) and production cost is high
Solution Approach 1:
The patent changes the protecting group from TMS to TBDMS, and modifies the reaction conditions including using a different base (LiHMDS instead of n-BuLi) and adjusting temperatures, which collectively improve the reaction yield from 25% to over 90% while reducing production costs through better atom economy and fewer purification steps
Solution Approach 2:
The patent employs a readily available and inexpensive protecting group (TBDMS) that can be easily installed and removed, replacing the more costly and less efficient TMS protecting group approach, thereby reducing overall manufacturing costs while improving yield
2Reliability
If the amino group is protected with TMSCl through phenyl Grignard reagent at 0°C and then temperature is lowered to -20°C for addition reaction, then the yield increases to 40%, but the operation becomes cumbersome with frequent temperature changes and different Grignard reagents
Solution Approach 1:
The patent combines the protecting group installation and the addition reaction into a single operational sequence using one base (LiHMDS) and maintaining a consistent temperature regime, eliminating the need for separate Grignard reagent additions and frequent temperature changes required in previous methods
Solution Approach 2:
The patent uses LiHMDS as a universal base that serves multiple functions: it deprotonates the amine for protecting group installation and facilitates the subsequent addition reaction, replacing the need for multiple specialized reagents (phenyl Grignard and isopropyl Grignard) with a single versatile reagent system
3Reliability
If more than two metal reagents or different temperatures are used for protection and addition reaction, then the yield is improved to 40-60%, but the operation remains cumbersome and is not conducive to scale-up synthesis
Solution Approach 1:
The patent performs the protecting group installation as a preliminary step that sets up the molecule for the subsequent addition reaction under optimized conditions, allowing the entire sequence to be conducted in a streamlined manner that is amenable to scale-up synthesis
Solution Approach 2:
The patent optimizes reaction parameters including using LiHMDS as base, controlling temperature at -78°C during addition, and employing TBDMS protecting group, which collectively achieve yields of 40-60% while creating a robust protocol that can be easily scaled up for industrial production
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 achieves a high yield of at least 40%, is operationally simple, uses a single metal reagent, and is suitable for scale-up, reducing production costs and enhancing drug accessibility.
Implementation Method 1
in the presence of a secondary amine represented by Formula 4, a metal lithium reagent and 1,2-bis(chlorodimethylsilyl)ethane, allowing a compound represented by Formula 1 to react with the compound represented by Formula II to generate the C-nucleoside compound represented by Formula III
Implementation Method 2
allowing for a bis-silicon protection and lithium-halogen exchange
Data Source
AI summary
Disclosed is a method for preparing a C-nucleoside compound represented by Formula (III) or salt thereof. The present method has a high reaction yield, is simple to operate, uses a single metal reagent, has stable reaction temperature conditions, does not require frequent changes to the reaction system during the operation process, is suitable for scale-up synthesis, is suitable for large-scale production of Remdesivir, and has low costs.