Fluorinated Nitroso Pyrimidine Intermediate for Vericiguat Synthesis
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Solution Overview
Problem
Existing synthetic pathways for vericiguat suffer from low overall yield and require a large number of steps, making them inefficient and costly.
Innovation Solution
A novel intermediate, 2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-nitrosopyrimidin-4,6-diamine, is used to synthesize vericiguat in two steps with a yield greater than 65%, involving the conversion of a nitrous group to an amino group and subsequent reaction with methyl chloroformate or dimethyl dicarbonate.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional synthetic pathways are used for vericiguat preparation, then the synthesis can be completed, but the overall yield is low and the number of steps is large
Solution Approach 1:
The patent combines multiple synthetic steps into a single step by using a pre-formed amidinium salt intermediate that contains both the pyrimidine ring and the phenyldiazine group in one molecule. This merging of steps directly addresses the technical contradiction by reducing the number of operations while maintaining high yield.
Solution Approach 2:
The patent employs preliminary action by preparing the amidinium salt intermediate with the phenyldiazine group already in place before the final reduction step. This pre-preparation of the intermediate structure allows the final step to directly form vericiguat without requiring multiple separate operations, thus reducing the overall number of steps while maintaining high yield.
2Productivity
If conventional synthetic pathways are used for vericiguat preparation, then the synthesis can be completed, but the process is inefficient and costly
Solution Approach 1:
The patent merges multiple synthetic operations into a single step, thereby reducing the total energy consumption and resource loss associated with multiple heating, cooling, filtration, and purification cycles. This directly improves synthesis efficiency while reducing energy loss.
Solution Approach 2:
The patent improves efficiency by using a synthetic pathway that avoids the need to discard and reprocess multiple intermediate substances. The direct formation of vericiguat from the pre-formed intermediate minimizes material loss and reduces the energy required for waste disposal and material recovery operations.
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 significantly improves the yield and reduces the number of steps required for vericiguat synthesis, achieving a high yield of 95% in two steps, thus enhancing efficiency and cost-effectiveness.
Implementation Method 1
converting a nitrous group to an amino group
Implementation Method 2
subsequent reaction with methyl chloroformate or dimethyl dicarbonate
Data Source
AI summary
The invention is directed to a 2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-nitrosopyrimidin-4,6-diamine, or a salt thereof, to a method for its preparation, to the use of said compound in the preparation of vericiguat, to a new salt of vericiguat and trifluoroacetic acid, to the preparation of said salt of vericiguat and trifluoroacetic acid and to a process of preparing vericiguat from the trifluoroacetic acid salt of vericiguat.