Influence of the solvent on the crystallization of multi-component compounds comprising chiral molecules
(2024)
Files
Thesis_JdeMeester_Influenceofthesolventonthecrystallizationofmulti-componentcompoundscomprisingchiralmolecules.pdf
Open Access - Adobe PDF
- 9.24 MB
Details
- Authors
- Supervisors
- Leyssens, Tom
- Abstract
- Crystallization-based resolution methods are of utmost importance in industrial applications. Yet the understanding of the solvent influence in such processes remains poorly developed in the literature. Therefore, this work investigates the pivotal role of solvent in crystallization phenomena, focusing specifically on chiral molecules and on the development of resolution methodologies. The present study investigates three distinct systems. First, we meticulously explored the interplay between two racemic compounds, 1,1'-bi-2-naphtol (BINOL) and trans-cyclohexane-1,2-diamine, across various solvent environments. We highlighted how the nature of the solvent can have an important impact on the type of multicomponent solid obtained. Complete characterization of the obtained phases demonstrated that when developing a chiral resolution process, the solvent must be chosen carefully. This chapter emphasizes both the potential complexity introduced by the solvent and the profound impact of the solvent choice on the efficiency of a chiral resolution process. Second, diastereomeric resolution of BINOL using (R,R)-N,N′-dimethyl-1,2-diphenylethane-1,2-diamine as a resolving agent was developed in two achiral solvents, toluene and benzene. We discovered how the solvent choice dictates the obtained thermodynamic form, enabling to recover by crystallization either (S)- or (R)-BINOL, when using respectively toluene or benzene. Isoplethal ternary diagrams were constructed in order to optimize resolution conditions and facilitate scalability. Finally, we developed the preferential crystallization of the Mandelic acid-Nefiracetam cocrystal-conglomerate system, using pressurized CO2 as an antisolvent. First, we demonstrated the proof-of-concept of preferential crystallization through pressurized CO2 and studied various parameters influencing resolution. Secondly, system optimization enabled simultaneous resolution of both enantiomers. These investigations underline the underestimated role of solvent, highlighting its potential as a passive medium or as an active tool, shaping resolution processes and allowing to tailor the desired crystalline forms to target a specific enantiomer.
- Affiliations
Citations
de Meester, J. (2024). Influence of the solvent on the crystallization of multi-component compounds comprising chiral molecules. https://hdl.handle.net/2078.5/233138