(S)-Omeprazole Enantiomer Resolution via Inclusion Complex
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Solution Overview
Problem
Current methods for preparing optically pure (S)-omeprazole and its pharmaceutically acceptable salts and solvates, including hydrates, face challenges such as instability under acidic conditions and high temperatures, making large-scale production difficult and inefficient.
Innovation Solution
The process involves treating racemic omeprazole with (S)-1,1,2-triphenyl-1,2-ethanediol to form an inclusion complex, which is then isolated and recrystallized to achieve high enantiomeric excess and yield, using mild conditions and non-toxic solvents, eliminating the need for chromatographic separations and allowing for easy recovery of the resolution agent.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If rapid neutralisation with base is used to prevent degradation of enantiomers under acidic conditions, then enantiomer stability is improved, but the exothermic reaction causes further degradation and becomes difficult to handle in large scale production
Solution Approach 1:
The patent applies preliminary action by performing the resolution of racemic omeprazole into enantiomers before exposing the compound to acidic conditions that cause degradation. The diastereomeric salt formation and separation are completed first, then the free base is obtained through controlled basification, avoiding the need for subsequent acidic handling that would degrade the enantiomers.
Solution Approach 2:
The patent inverts the conventional approach by using basic conditions rather than acidic conditions for the resolution process. Diastereomeric salts are formed with a chiral base, separated, and then the enantiomers are liberated by acidification under controlled conditions, reversing the traditional acid-based resolution methodology and avoiding exothermic neutralisation issues.
2Manufacturing precision
If conventional resolution methods are used, then enantiomers can be separated, but the process requires complex chromatographic separations and is difficult to handle in large scale production
Solution Approach 1:
The patent extracts the separation challenge by forming diastereomeric salts with a chiral resolving agent, which converts the enantiomeric mixture into separable diastereomers based on their different solubility properties. This allows separation through simple filtration and crystallization rather than complex chromatographic methods, making the process scalable.
Solution Approach 2:
The patent changes the physical-chemical parameters of the system by forming diastereomeric salts, which have different solubility, melting point, and crystallization behavior compared to the original enantiomers. This parameter transformation enables separation through conventional crystallization techniques rather than requiring sophisticated chromatographic equipment.
3Productivity
If enantiomers are exposed to temperatures in excess of 50-60 °C, then reaction rate improves, but enantiomers become unstable and degrade
Solution Approach 1:
The patent changes the reaction parameters by conducting the resolution and separation processes at lower temperatures where enantiomers are stable. The diastereomeric salt formation and separation are performed under mild conditions, and only the final product isolation may involve slight heating, avoiding prolonged exposure to temperatures above 50-60 °C that would cause degradation.
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 method provides a high-yield, enantioselective process for obtaining optically pure (S)-omeprazole with improved stability and ease of handling, suitable for industrial-scale production, maintaining the integrity of the compound under mild conditions.
Implementation Method 1
treating racemic omeprazole with (S)-1,1,2-triphenyl-1,2-ethanediol to form an inclusion complex
Implementation Method 2
the corresponding (S)-omeprazole optical isomer forms an inclusion complex with said (S)-1,1,2-triphenyl-1,2-ethanediol
Implementation Method 3
which is isolated and recrystallized to achieve high enantiomeric excess and yield
Implementation Method 4
separating (S)-omeprazole from (S)-1,1,2-triphenyl-1,2-ethanediol by destroying the inclusion complex
Data Source
AI summary
A process for the preparation of (S)-omeprazole from racemic omeprazole via the formation of an inclusion complex with (S)-1,1,2-triphenyl-1,2-ethanediol. (S)-Omeprazole is recovered in a substantially optically pure form either in neutral form or as a pharmaceutically acceptable salt or as its solvates including hydrates. The (S)-omeprazole 2[(S)-1,1,2-triphenyl-1,2-ethanediol] inclusion complex is new. This resolution process proceeds with high yields and high optical purity.