Novel methods and processes for the chiral resolution of fine chemicals

Previously held under moratorium from 1st March 2021 until 1st March 2023Chiral molecules occur in left- and right-handed configurations that can be considered as mirror images (enantiomers), and that, like hands, cannot be superimposed onto each other. Despite their similarity, the biological activity of enantiomers inside living organisms can be completely different. While one enantiomer may have a desirable therapeutic effect, the other may induce no response or even be harmful. Most pharmaceuticals and agrochemicals are chiral. The search of this specificity at the molecular level led to the development of many asymmetric syntheses. However, the enantioselective synthetic approach is not always possible and the mixture of equal amounts of both enantiomers (racemate) is obtained instead. Then, the separation of these enantiomers, known as chiral resolution, becomes the alternative pathway. Chiral resolution techniques have already been developed, but they still present some limitations. For that, the aim of this thesis is to develop novel methodologies and processes that integrate membrane filtration, crystallisation, and extraction technologies for the chiral resolution of fine chemical racemates. In chapter 3, the effects of pH and temperature on the solubility and phase diagrams of three racemic compound-forming systems are described. This preliminary study of effects permits the development of a method to accurately estimate the eutectic points and phase diagrams of these systems. Additionally, the method also gives the possibility to determine the class of crystal lattice (conglomerate, racemic compound, or solid solution) of any chiral compound. The ultimate objective of this chapter is to provide a workflow process to determine fast and accurately the phase diagrams of racemic compounds. The chiral resolution of conglomerates has been successful by means of crystallisationbased techniques such as preferential crystallisation. Nevertheless, this type of chiral compounds alongside solid solutions are rare with racemic compounds being the most abundant. The latter class requires an initial enantiomeric enrichment which must go beyond the eutectic composition to after being able to selectively crystallise an enantiopure product. The main objective of chapter 4 is to assess if the combination of membrane filtration and crystallisation technologies enables the continuous chiral resolution of racemic compounds. This has been carried out through computerised modelling and optimisation of the integrated VII process and has shown potential to further explore and test the process with other chiral systems. The separation of enantiomers can also be attempted by leveraging the potential distinctive enantiospecific interactions between enantiomers and chiral solvents. In that way, chapter 5 evaluates the chiral recognition capacity of the relatively new chiral solvent cyrene and finds its potential for chiral resolution process applications founded on both enantioselective liquidliquid extraction and crystallisation. The work in this thesis has achieved its aim in developing novel methodologies and processes for the chiral resolution of fine chemical racemates by providing a less laborious workflow process for the fast and accurate determination of ternary phase diagrams of racemic compounds, which has served to propose a novel chiral resolution process for this class of chiral compounds that integrates both membrane filtration and crystallisation technologies. In addition, the enantiomeric discrimination power found in the chiral solvent cyrene has made possible to propose this solvent for its use in the separation of enantiomers by means of enantioselective liquid-liquid extraction and crystallisation. The findings described in this text will then facilitate the study, understanding, and characterisation of chiral resolution processes based on enantioselective interactions in separation techniques, such as membrane filtration, crystallisation, and extraction. The new methodologies and processes developed in this thesis have the potential to address current and future challenges in the separation of enantiomers, which is of high interest for the fine chemical industry.Chiral molecules occur in left- and right-handed configurations that can be considered as mirror images (enantiomers), and that, like hands, cannot be superimposed onto each other. Despite their similarity, the biological activity of enantiomers inside living organisms can be completely different. While one enantiomer may have a desirable therapeutic effect, the other may induce no response or even be harmful. Most pharmaceuticals and agrochemicals are chiral. The search of this specificity at the molecular level led to the development of many asymmetric syntheses. However, the enantioselective synthetic approach is not always possible and the mixture of equal amounts of both enantiomers (racemate) is obtained instead. Then, the separation of these enantiomers, known as chiral resolution, becomes the alternative pathway. Chiral resolution techniques have already been developed, but they still present some limitations. For that, the aim of this thesis is to develop novel methodologies and processes that integrate membrane filtration, crystallisation, and extraction technologies for the chiral resolution of fine chemical racemates. In chapter 3, the effects of pH and temperature on the solubility and phase diagrams of three racemic compound-forming systems are described. This preliminary study of effects permits the development of a method to accurately estimate the eutectic points and phase diagrams of these systems. Additionally, the method also gives the possibility to determine the class of crystal lattice (conglomerate, racemic compound, or solid solution) of any chiral compound. The ultimate objective of this chapter is to provide a workflow process to determine fast and accurately the phase diagrams of racemic compounds. The chiral resolution of conglomerates has been successful by means of crystallisationbased techniques such as preferential crystallisation. Nevertheless, this type of chiral compounds alongside solid solutions are rare with racemic compounds being the most abundant. The latter class requires an initial enantiomeric enrichment which must go beyond the eutectic composition to after being able to selectively crystallise an enantiopure product. The main objective of chapter 4 is to assess if the combination of membrane filtration and crystallisation technologies enables the continuous chiral resolution of racemic compounds. This has been carried out through computerised modelling and optimisation of the integrated VII process and has shown potential to further explore and test the process with other chiral systems. The separation of enantiomers can also be attempted by leveraging the potential distinctive enantiospecific interactions between enantiomers and chiral solvents. In that way, chapter 5 evaluates the chiral recognition capacity of the relatively new chiral solvent cyrene and finds its potential for chiral resolution process applications founded on both enantioselective liquidliquid extraction and crystallisation. The work in this thesis has achieved its aim in developing novel methodologies and processes for the chiral resolution of fine chemical racemates by providing a less laborious workflow process for the fast and accurate determination of ternary phase diagrams of racemic compounds, which has served to propose a novel chiral resolution process for this class of chiral compounds that integrates both membrane filtration and crystallisation technologies. In addition, the enantiomeric discrimination power found in the chiral solvent cyrene has made possible to propose this solvent for its use in the separation of enantiomers by means of enantioselective liquid-liquid extraction and crystallisation. The findings described in this text will then facilitate the study, understanding, and characterisation of chiral resolution processes based on enantioselective interactions in separation techniques, such as membrane filtration, crystallisation, and extraction. The new methodologies and processes developed in this thesis have the potential to address current and future challenges in the separation of enantiomers, which is of high interest for the fine chemical industry