Esomeprazole Optical Resolution via BINOL Inclusion Complex
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing processes for the optical resolution of omeprazole to produce esomeprazole are hindered by the use of harmful solvents and the sensitivity of esomeprazole to high temperatures, leading to decomposition.
Innovation Solution
A process involving the formation of an optically pure BINOL inclusion complex with omeprazole using low concentrations of alkali metal hydroxide or alcoholate in a solvent, followed by precipitation with an antisolvent or cooling, which avoids harmful solvents and moderate temperatures to achieve high purity esomeprazole-BINOL complex.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If harmful solvents such as benzene or toluene are used to form BINOL inclusion complex, then optical resolution of omeprazole can be achieved, but the process introduces toxic and harmful factors
Solution Approach 1:
The patent changes the solvent parameter from harmful aromatic solvents (benzene, toluene) to safe aliphatic solvents (hexane, heptane, cyclohexane, dichloromethane). This parameter substitution maintains the ability to form BINOL inclusion complexes for optical resolution while eliminating the toxic effects of aromatic solvents, thus resolving the contradiction between achieving optical purity and avoiding harmful factors.
2Ease of manufacture
If esomeprazole-BINOL complex is precipitated from hot solution, then crystallization can be initiated, but decomposition occurs due to temperature sensitivity
Solution Approach 1:
The patent performs preliminary action by adding the BINOL enantiomer to the omeprazole solution before heating, allowing the inclusion complex to form in advance. The mixture is then heated to initiate crystallization of the pre-formed complex, which reduces the exposure time of esomeprazole to high temperatures and minimizes decomposition, thus resolving the contradiction between enabling crystallization and maintaining stability.
3Ease of operation
If high concentrations of alkali metal hydroxide or alcoholate are used, then solubilizing effect is enhanced, but the complexity of process control increases
Solution Approach 1:
The patent applies partial action by using low concentrations of alkali metal hydroxide or alcoholate (0.005 to 0.7 molar ratio) instead of high concentrations. This partial use of the solubilizing agent is sufficient to enable the formation of BINOL inclusion complexes and subsequent crystallization, while avoiding the need for complex process control that would be required at higher concentrations, thus resolving the contradiction between ease of operation and device complexity.
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 achieves esomeprazole-BINOL complex with optical purity exceeding 99.0% and chemical purity of 99.5% without using harmful solvents, allowing for easy separation and recovery of esomeprazole at moderate temperatures, minimizing decomposition.
Implementation Method 1
preparing (i) a solution of omeprazole and BINOL enantiomer in a solvent containing low concentrations of alkali metal hydroxide or alcoholate
Implementation Method 2
precipitating esomeprazole BINOL complex by treating the solution with an antisolvent or cooling the reaction mixture to initiate crystallization
Implementation Method 3
cooling the reaction mixture to initiate crystallization
Data Source
Figure 1
AI summary
The invention relates to an improved process for preparation of esomeprazole or salts thereof by optical resolution of omeprazole with BINOL (1,1'-bi-2-naphthol).