Selexipag Preparation via Single Ester Solvent System
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Solution Overview
Problem
The existing process for preparing Selexipag is cumbersome and time-consuming, requiring multiple solvents and column purification, making it unsuitable for industrial and commercial scales, and results in low yields and purity.
Innovation Solution
A process involving reacting compounds of formula II and III in the presence of a condensing agent and a solvent, with pH adjustment using a buffer, followed by solvent removal and isolation, which also includes the formation of crystalline and amorphous Selexipag salts using specific bases and solvents, reducing the need for column purification and using a single solvent system.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the prior art process uses multiple solvents (tetrahydrofuran and diethylether) for condensation and work-up, then the reaction can proceed, but the process becomes cumbersome and time-consuming with minimum 32 hours reaction time
Solution Approach 1:
The patent changes the solvent parameter from traditional tetrahydrofuran/diethylether system to a single ester solvent system (ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, or ethyl formate). This parameter change reduces reaction time from minimum 32 hours to 6-24 hours while simplifying the work-up procedure by eliminating the need for multiple solvent removal steps and column purification.
Solution Approach 2:
The patent extracts and eliminates the need for column purification step from the process. By using the ester solvent system with appropriate bases (triethylamine, isopropylamine, tri n-butylamine, N-methylmorpholine, or diisopropylethylamine), the reaction mixture can be directly worked up by simple filtration and solvent removal, removing the tedious column chromatography step entirely.
2Manufacturing precision
If column purification is used to remove 1,1'-carbonyldiimidazole, then purity can be achieved, but the process becomes tedious and unsuitable for commercial scale
Solution Approach 1:
The patent removes the column purification step from the manufacturing process. By selecting ester solvents and appropriate bases that facilitate direct precipitation or filtration of impurities, the process achieves the required purity through simple work-up procedures suitable for commercial scale production.
Solution Approach 2:
The patent changes the purification approach from column chromatography to a precipitation/filtration method by adjusting the solvent system parameters. The ester solvent combined with specific bases creates conditions where impurities precipitate or can be easily separated by filtration, achieving high purity without complex purification steps.
3Productivity
If multiple solvents are used for condensation and work-up, then the reaction can be completed, but the process is not suitable for industrial and commercial scales
Solution Approach 1:
The patent merges the condensation reaction medium and the work-up solvent into a single ester solvent system. The same ester solvent (ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, or ethyl formate) serves both as the reaction medium and the extraction solvent, eliminating the need for separate solvent systems and simplifying the overall process for industrial scalability.
Solution Approach 2:
The ester solvent system performs multiple functions: it acts as the reaction medium for condensation, the extraction solvent for work-up, and the medium for direct crystallization or filtration. This multi-functional solvent system eliminates the need for multiple solvent transfers and removal steps, making the process suitable for commercial 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
This process significantly reduces reaction time, increases yield and purity, and allows for the production of Selexipag in both crystalline and amorphous forms with enhanced stability and commercial viability.
Implementation Method 1
reacting the compound of formula II with a compound of formula III in the presence of a condensing agent
Implementation Method 2
adjusting the pH of the reaction mass by using a buffer, acetic acid
Implementation Method 3
reacting the compound of formula II with a compound of formula III in the presence of a condensing agent and a solvent
Implementation Method 4
the formation of crystalline and amorphous Selexipag salts using specific bases and solvents
Data Source
AI summary
The present invention relates to a process for the preparation of amorphous Selexipag from Selexipag crystalline salts using a solvent.