Chiral Resolution of Cibenzoline Succinate for High Enantiomeric Purity
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Solution Overview
Problem
There is a lack of commercially viable and industrially feasible methods for producing enantiomerically pure (−)-Cibenzoline succinic acid salt with high purity and yield, as existing processes suffer from low enantiomeric excess, use of expensive reagents, and high impurity levels.
Innovation Solution
A novel process involving the preparation of (−)-Cibenzoline succinic acid salt through the steps of converting racemic Cibenzoline succinic acid salt to racemic Cibenzoline free base, forming racemic Cibenzoline·chiral acid salt, isolating (−)-Cibenzoline·chiral acid salt, and then converting it to (−)-Cibenzoline succinic acid salt using suitable solvents and bases, allowing for high chiral purity and yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing synthesis processes are used to prepare enantiomerically pure (−)-Cibenzoline succinic acid salt, then some enantiomeric purity can be achieved, but the processes suffer from low enantiomeric excess, use of expensive reagents, and high impurity levels
Solution Approach 1:
The patent employs a chiral resolving agent as an intermediary substance to separate the racemic mixture into enantiomerically pure (−)-Cibenzoline succinic acid salt. The resolving agent forms diastereomeric salts with the racemic base, allowing selective crystallization and purification of the desired enantiomer, thereby achieving high enantiomeric purity without complex multi-step syntheses
Solution Approach 2:
The patent utilizes changes in physical and chemical parameters during the resolution process, including temperature variations during crystallization, pH adjustments during salt formation, and solvent selection. These parameter changes enable selective precipitation and purification of the (−)-enantiomer from the racemic mixture, achieving high purity with a straightforward single-step process
2Manufacturing precision
If conventional resolution methods are applied, then enantiomeric purity can be improved, but the process complexity and cost increase due to multiple steps and expensive reagents
Solution Approach 1:
The patent extracts and isolates the (−)-Cibenzoline succinic acid salt directly from the racemic mixture through a single resolution step using a chiral resolving agent. This extraction approach avoids the need for multiple synthesis steps and purification operations, achieving high enantiomeric excess while maintaining process simplicity
Solution Approach 2:
The patent performs preliminary action by forming diastereomeric salts before separation. By pre-reacting the racemic base with the chiral resolving agent, the mixture is transformed into separable diastereomers that can be easily separated by crystallization, thereby simplifying the overall process and avoiding complex multi-step syntheses
3Ease of manufacture
If racemic Cibenzoline succinic acid salt is used, then manufacturing is simpler, but pharmacokinetic complexity and side effects increase due to presence of both enantiomers
Solution Approach 1:
The patent converts the harmful presence of unwanted enantiomers in racemic mixtures into a beneficial resolution process. By using a chiral resolving agent, the racemic mixture is transformed into enantiomerically pure (−)-Cibenzoline succinic acid salt, eliminating the harmful effects of the (+)-enantiomer while maintaining manufacturing simplicity through a single resolution step
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 process enables the production of (−)-Cibenzoline succinic acid salt with pharmaceutically acceptable optical purity and high yield, suitable for mass production and commercial applications, with potential benefits including simpler pharmacokinetics and reduced side effects.
Implementation Method 1
treating the racemic Cibenzoline free base with a chiral acid in the presence of a solvent to form a racemic Cibenzoline·chiral acid salt, isolating the (−)-Cibenzoline·chiral acid salt
Implementation Method 2
treating the (−)-Cibenzoline·chiral acid salt with a base to prepare the (−)-Cibenzoline free base
Implementation Method 3
treating the (−)-Cibenzoline free base with succinic acid in the presence of a solvent to prepare the (−)-Cibenzoline succinic acid salt
Data Source
AI summary
The present invention relates to a crystal form of (−)-Cibenzoline succinate. In addition, the present invention relates to a method for preparing (−)-cibenzoline succinate having a chiral purity of 99.9% or higher. Additionally, the present invention provides a method for preparing (−)-cibenzoline succinate and a crystal form thereof.