Remdesivir Intermediate Coupling With Accessible Organic Bases
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for producing remdesivir intermediates require expensive and hard-to-access reagents, extreme reaction conditions, and undesirable steps, making industrial-scale production challenging.
Innovation Solution
A process involving the coupling of specific intermediates (compounds of formula IV and III) using less expensive and accessible reagents, with controlled reaction conditions, and reduced steps, including protection, coupling, and cyanation steps, facilitated by batch or continuous flow methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing methods are used for producing remdesivir intermediates, then the coupling reaction can be performed, but expensive and hard-to-access reagents are required
Solution Approach 1:
The patent replaces expensive and hard-to-access reagents with cheaper, more accessible alternatives. Specifically, it substitutes rare earth metal halides (LaCl3, NdCl3, YCl3, CeCl3) with conventional organic bases such as triethylamine, diisopropylethylamine, or pyridine, which are commercially available and easier to handle. This substitution maintains the coupling reaction's effectiveness while significantly improving reagent accessibility and reducing costs.
2Reliability
If existing methods are used for producing remdesivir intermediates, then the coupling reaction can be performed, but extreme reaction conditions are required
Solution Approach 1:
The patent modifies the reaction conditions by eliminating the requirement for extreme temperatures and rare earth metal catalysts. The coupling reaction is performed under milder conditions using conventional organic bases at standard temperatures, thereby maintaining reaction success while reducing the severity of reaction conditions. This parameter change makes the process more suitable for industrial-scale production.
3Reliability
If existing methods are used for producing remdesivir intermediates, then the coupling reaction can be performed, but the number of steps is increased
Solution Approach 1:
The patent combines the protection and coupling steps into a more streamlined sequence. By using readily available protected ribonolactone derivatives and performing the coupling reaction directly with conventional bases, the method reduces the number of intermediate steps required. This merging of steps improves synthesis efficiency and productivity while maintaining reaction completion reliability.
4Reliability
If existing methods are used for producing remdesivir intermediates, then the coupling reaction can be performed, but costly reagents are required
Solution Approach 1:
The patent replaces costly rare earth metal halides with inexpensive conventional organic bases. The use of triethylamine, diisopropylethylamine, or pyridine instead of LaCl3, NdCl3, YCl3, or CeCl3 dramatically reduces material costs while maintaining product quality. This substitution makes the synthesis process economically viable for large-scale 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
Enables efficient and scalable production of remdesivir intermediates with improved yields, eliminating the need for costly and difficult-to-obtain reagents and harsh conditions.
Implementation Method 1
the coupling reaction between the protected ribonolactone and 7-bromo-pyrrolo[2,1 -f][1,2,4]triazin-4-ylamine is carried out by lithiation
Implementation Method 2
the cyanation step (Reaction Scheme 2)
Data Source
Figure 1
AI summary
The present invention relates to a process for the preparation of a compound of formula (I) and to novel intermediates of the synthesis, wherein X is hydrogen, bromine or iodine; R1 is a protecting group, R2 is hydrogen or a protecting group, and PG is a protecting group.