Finerenone Racemate Resolution with Diastereomeric Tartaric Esters
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Solution Overview
Problem
Existing methods for resolving racemic finerenone using D-dibenzoyltartaric acid as a resolving agent result in low isomer recovery rates and significant resolution losses, requiring multiple dissociations to reduce the chiral substituted tartaric ester content below 0.15%, leading to inefficiencies and increased costs.
Innovation Solution
A method utilizing chiral substituted tartaric esters, such as D-di-o-methylbenzoyltartaric acid, for resolving racemic finerenone, optimizing stoichiometric ratios and solvent mixtures to achieve almost quantitative diastereomer salt precipitation, followed by a single dissociation step with bases like sodium phosphate to obtain high-purity enantiomers with minimal residual tartaric ester content.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If D-dibenzoyltartaric acid is used as a resolving agent, then the racemate can be resolved into enantiomers, but the isomer recovery rate is low and resolution loss is significant
Solution Approach 1:
The patent changes the chemical structure parameters of the resolving agent by introducing different substituents (methoxycarbonyl, methyl, halogen atoms) on the benzoyl groups of tartaric acid. This structural modification optimizes the interaction between the resolving agent and the racemate, enabling almost quantitative precipitation of the desired diastereomer salt while maintaining high enantiomeric purity, thus resolving the contradiction between manufacturing precision and productivity
2Manufacturing precision
If multiple dissociations are performed to reduce tartaric ester content below 0.15%, then the purity of the final product is improved, but the process time and production cost increase
Solution Approach 1:
The patent employs a specially designed chiral substituted tartaric ester resolving agent that forms diastereomer salts with almost quantitative precipitation efficiency. This allows the resolving agent to be effectively removed in a single dissociation step, eliminating the need for multiple repeated dissociations. The resolving agent serves its purpose efficiently and is then discarded, reducing both process time and production cost while maintaining high product purity
3Manufacturing precision
If multiple dissociations are required to reduce resolving agent content, then the residual tartaric ester is reduced, but the production cost increases due to increased waste and processing steps
Solution Approach 1:
The patent modifies the chemical parameters of the resolving agent by introducing specific substituents that enhance the precipitation efficiency of the diastereomer salt. This optimization allows for complete separation in a single step, minimizing the residual tartaric ester content to below 0.05% while avoiding the need for multiple dissociation cycles, thereby reducing production cost and waste generation
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 approach significantly enhances enantiomeric purity (>97% e.e.) and reduces production costs by minimizing tartaric ester residue to less than 0.05%, thus improving efficiency and reducing waste through a single dissociation process.
Implementation Method 1
Reaction of a racemate represented by formula (V) with a chiral substituted tartaric ester represented by formula (VIa) or (VIb) results in the formation of four options of diastereomer salts (VIIa, VIIb, VIIc and VIId)
Implementation Method 2
The diastereomer salt of formula (VIIa) precipitates almost quantitatively from the solution and can then be separated from the solution, for example by filtration
Implementation Method 3
In the step of treating the diastereoisomer salt with a base, multiple dissociations are usually required to reduce the content of the chiral substituted tartaric ester as the resolving agent to less than 0.15%
Data Source
Figure 1
AI summary
The present invention provides a method for preparing finerenone by means of resolving a racemate with a diastereomeric tartaric ester, and also relates to diastereomer salts (VIIa), (VIIb), (VIIc) and/or (VIId). The resolving method uses a chiral substituted tartaric ester represented by general formula (VIa) or (VIb) as a resolving agent to resolve a racemate represented by formula (V) to obtain a compound represented by formula (Va) and/or (Vb). The racemate is firstly added into a solvent mixture to be heated until completely dissolved; then the resolving agent is added to obtain a homogeneous system; and resolution is performed by stirring for crystallization. The optimization of the feeding sequence can ensure sufficient salt formation, thereby greatly shortening the time for crystallization. In a basic dissociation step, a crude product with very high chemical purity and enantiomeric purity can be obtained by means of one-time dissociation, and the content of the tartaric ester as the resolving agent is less than 0.05%, such that the three wastes caused by multiple dissociations are avoided, and the production cost is greatly reduced.