Synthesis and Solid State Pharmaceutical Centre (SSPC) - Doctoral Theses

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    Cocrystallization of organic compounds
    (University College Cork, 2023) Huang, Shan; Lawrence, Simon; Science Foundation Ireland
    This thesis discusses the synthesis, characterization, and properties of multi-component crystalline materials of active pharmaceutical ingredients. A special emphasis is placed on cocrystallization, which is the supramolecular phenomenon of aggregation of two or more different chemical entities in a crystalline lattice through non-covalent interactions. This research has been divided into seven chapters. Chapter 1 gives an overview of the concept of multi-component crystalline materials and cocrystallization, where the design, methodology, characterization and application of cocrystals are also included. Chapter 2 discusses the synthesis of multi-component crystal forms of a sulfonamide compound, sulfasalazine, through cocrystallization and explores the crystal structure landscape of sulfasalazine. Furthermore, the differences are illustrated between cocrystals and salts of sulfasalazine via structural analysis, Hirshfeld surface analysis and frontier molecular orbitals analysis. Chapter 3 investigates the hydrogen bonding interactions in cocrystals of a frequently used sulfonamide compound, sulfaguanidine, by both experimental methods and theoretical calculations including the analysis of Hirshfeld surface, molecular electrostatic potential surfaces and quantum theory of atoms in molecules. Chapter 4 focuses on pharmaceutical salts of piroxicam and meloxicam with three basic organic counterions, respectively. The solubility of six salts and two parent drugs in sodium phosphate solution were conducted. Furthermore, piroxicam and its salts exhibited different luminescent properties, thus, the different luminescent mechanisms were discussed. Chapter 5 explores cocrystallization of 19 natural L-amino acids and both enantiomers of four pharmaceutically relevant chiral compounds. The formation of diastereomeric or enantiospecific systems were explored using an examination of their hydrogen bonding motifs. Chapter 6 investigates the formation of diastereomeric cocrystal pairs of S mandelamide with both enantiomers of mandelic acid and proline, respectively. In addition, the crystal structures of (±)-mandelamide, S-mandelamide and enantio-enriched mandelamide (94 S:6 R) were determined. Detailed crystal structural analyses together with Hirshfeld surface analysis were carried out. Chapter 7 summarizes the main findings of the entire work and examines future work, such as the use of ternary phase diagrams to assist in developing chiral separation processes.
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    Cocrystallising acids and amides: towards pharmaceutical cocrystals
    (University College Cork, 2021-07-20) Stokes, Stephen P.; Lawrence, Simon E.; Maguire, Anita; Science Foundation Ireland
    The work presented in this dissertation focuses on the molecular features of small molecules and their interactions with pharmaceutically relevant molecules. Emphasis is placed on cocrystallisation; a method that facilitates the formation of multicomponent forms of molecules with non-ionisable or weakly ionisable functional groups. This research has been divided into nine chapters. Chapter 1 describes the concept of crystallisation and introduces supramolecular chemistry. Through the explanation of hydrogen and halogen bonding, which is prominent throughout this work, the concept of supramolecular synthons is unveiled for multicomponent compounds. Finally, applications of cocrystals involving pharmaceutically industrially relevant compounds amongst others are discussed. Chapter 2 gives an overview of the general procedures carried out in this work. Furthermore, a list of the analytical equipment employed is described. Chapter 3 initially describes the crystal landscape of the secondary amide γ-lactam, 2-pyrrolidone, 1, with extension to other lactam systems. This compound is of relevance as it is used routinely as a high boiling solvent in the pharmaceutical industry. A cocrystal screen of 1 was carried out with a range of amide and carboxylic acid based coformers, and fenamic acid active pharmaceutical ingredients (APIs). The common structural motifs of the successfully resolved single crystals were grouped and discussed, and the robustness of the cocrystal forming abilities of 1 demonstrated. Chapter 4 discusses the benzene fused γ-lactam, 2-oxindole, 2, which is the benzene fused analogue of 1. An initial polymorphic screen was employed with a subsequent cocrystal screen of 2 with a range of coformers similar to 1. From this, an investigation into the solid-state similarities between cocrystals of 1 and 2 was conducted, revealing both similarities and variations in the observed motifs. Chapter 5 focuses on a molecule of pharmaceutical relevance, namely modafinil, 3, an anti-narcoleptic drug. In an attempt to utilise the halogen bonding potential of both 3 and 1,4-diiodotetraflourobenzene, the discovery of a dihydrate of 3 is described with characterisation of the resultant solid-state structure. Chapter 6 focuses on 6-propyl-2-thiouracil, 4, an API used in the treatment of Graves’ disease. A cocrystal screening involving acids, amides, fenamic acids and other API molecules was conducted. The motifs of successful single crystal structures are discussed and the structural properties rationalised. Chapter 7 describes the synthetic strategies to synthesise four fenamic acid based molecules, two of which are novel molecules containing methylene linkers. Chapter 8 Conclusion summarising the main findings of the entire work. Chapter 9 Appendix
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    Telescoping of transition metal catalysed and biocatalysed reactions
    (University College Cork, 2020-11-10) Kelly, Áine; Moynihan, Humphrey A.; Science Foundation Ireland
    This thesis describes the telescoping reactions which exploit the diverse catalytic approaches of transition metal catalysis and biocatalysed processes. These processes would normally have conditions that are incompatible. Telescoping these processes into a single process will provide powerful enantioselectivity which exploits the efficiency of transition metal catalysis and the stereoselectivity of biocatalysis. Chapter one provides an overview of asymmetric synthesis, both –diazocarbonyl compound synthesis and reactions, and biotransformations. It also gives an overview of telescoping systems from the literature. The results of this research are discussed in both chapter two and three. Chapter two describes the initial work undertaken during this project including attempting intramolecular X–H insertion reactions and intramolecular C–H insertion and then the Baker’s yeast reduction of those products. The batchwise step–by–step transformations were undertaken initially and then telescoped together overcoming problems associated with the process. Chapter three describes the C–H intramolecular reactions with both rhodium (II) acetate and copper (II) triflate to produce a range of 2–benzenesulfonyl substituted cyclopentanone compounds. These compounds were then kinetically resolved via a Baker’s yeast mediated reduction. These individual steps were optimised before they were telescoped together. The range of 2–benzenesulfonyl substituted cyclopentanone compounds also underwent ring cleavage to give simple carboxylic acids which could then be desulfonylated to simple alcohol compounds with a stereocentre in the middle of the chain. Chapter four contains the full experimental details and spectral characterisation of all the compounds synthesised in this project, while the details of the chiral stationary phase HPLC analysis is included in the appendix.
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    Telescoping the synthesis and heterogeneous transition metal catalysed asymmetric transformations of α-diazoketones and α-diazoacetamides in continuous flow
    (University College Cork, 2020-09-17) Crowley, Daniel C.; Maguire, Anita; Irish Research Council
    This project aims to expand the extensive work carried out by the Maguire group on the synthesis and reactivity of α-diazocarbonyl compounds over the last 25 years, with primary focus on the intramolecular aromatic addition of α-diazoketones. This transformation is studied in depth with particular focus on exploiting contemporary techniques and methodologies, such as immobilised catalysis and continuous flow processing, to enhance the practical synthetic potential of this powerful transformation. Chapter 1 provides a literature review as background to this research project focussing, in particular, on methodologies for the synthesis of α-diazocarbonyl compounds and selectivity patterns in intramolecular aromatic addition processes. Chapter 2 focuses on the synthesis of α-diazocarbonyl compounds including α-diazoketones, α-diazo-β-ketonitriles, α-cyano-α-diazoamides and α-diazo-β-diketones. Traditional methods, such as acylation of diazoalkanes, are compared to newer, safer methods proceeding via diazo transfer on continuous flow, developed during this work. Specifically, continuous flow processing is utilised to harness the powerful synthetic utility of hazardous triflyl azide for α-diazocarbonyl compound synthesis, while offsetting the potential hazards inherent in its use. Chapter 3 describes the transition metal catalysed transformations of the α-diazocarbonyl compounds synthesised in Chapter 2. Results achieved with homogeneous copper–bis(oxazoline) catalyst systems are compared with those achieved with novel immobilised copper catalysts in both batch and continuous flow; the synthesis of the immobilised copper catalysts is also discussed. This is the first report of enantioselective, copper mediated aromatic addition using an immobilised catalyst in either batch or continuous flow with enantiopurities of up to 85% ee achieved. Furthermore, novel rhodium(II) mandelate catalysts, designed by the Maguire group, are applied across the array of α-diazocarbonyl compounds studied in the project, investigating their chemo- and stereoselectivity for intramolecular aromatic addition. Excellent control of both the chemo- and enantioselection (up to 89% ee) was achieved with the novel rhodium(II) mandelate catalysts. Finally, Chapter 4 combines the sulfonyl azide synthesis and α-diazocarbonyl compound synthesis explored in Chapter 2 with the transition metal catalysed transformation studied in Chapter 3. This furnishes a three-step telescoped sequence, whereby hazardous sulfonyl azides and α-diazocarbonyl compounds are synthesised in situ from readily handled starting iv materials, and, without being isolated or stored, are subjected directly to transition metal catalysis downstream, furnishing enantioenriched products. This chapter describes the steps taken in the process to ensure removal of by-products from upstream transformations, which would be detrimental to the transition metal catalysts, as well discussing the studies undertaken to ensure the safety of the transformation. This telescoped process realises the synthetic potential of these hazardous reagents in a manner safer than traditional batch processes, and the scale-up of the three-step telescoped process is successfully explored. Chapter 5 contains the full experimental details and spectroscopic characterisation of the compounds synthesised in this work.
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    Development and application of synthetic methodologies based on organosulfur and organophosphorus chemistry
    (University College Cork, 2020-05-22) Flynn, Aaran J.; Maguire, Anita; Science Foundation Ireland
    This thesis describes the development and application of synthetic methodologies based on various aspects of organosulfur and organophosphorus chemistry with a focus on understanding the underlying features and synthetic application. The first chapter systematically compiles and reviews, for the first time, the synthetic and mechanistic aspects of sulfonyl migrations over the last twenty years. Notably, the fact that these reactions are frequently described as ‘unusual’, ‘unprecedented’, ‘unexpected’, ‘serendipitous’ and ‘novel’ by authors, highlights that these potentially synthetically powerful transformations remain only partially understood. This introductory chapter explores the synthetic utility of sulfonyl migrations, while significant attention is afforded to the efforts made to elucidate their underlying mechanisms. This literature review was inspired by the observation of an ‘unprecedented’ carbon–carbon 1,2-sulfonyl migration in our work, which is discussed in detail in Chapter 2. The second chapter describes the use of α-thio-β-chloroacrylamides, a series of highly functionalised sulfur containing compounds pioneered in our group, as versatile dipolarophiles in [3+2] dipolar cycloaddition reactions. The [3+2] dipolar cycloaddition of highly reactive α-diazoalkanes with a range of dipolarophiles is well explored in the synthesis of pyrazolines and pyrazoles, however, analogous cycloadditions of electron deficient terminal diazo compounds such as α-diazoacetates, α-diazosulfones and α-diazoacetamides remains significantly less studied despite the synthetic and biological importance of ester, sulfone and amide moieties. The reactivity of these α-thio-β-chloroacrylamides at each of the sulfide, sulfoxide and sulfone oxidation levels with electron deficient α-diazoacetates, and related derivatives, is explored in the formation of densely functionalised pyrazole derivatives that would otherwise be difficult to obtain via traditional methods. Observation of an unprecedented 1,2-carbon to carbon sulfonyl migration is of particular interest. Significant attention is afforded to the elucidation of the tautomeric composition of the 3,4,5-substituted pyrazole products, while the synthetic versatility of these products is demonstrated via a series of derivatisations. Chapter three details the design and preparation of a series of acyclic α-carboxy nucleoside phosphonate derivatives envisaged to possess anti-viral and/or anti-cancer properties. This chapter details the use of Mitsunobu coupling and transition metal catalysed O–H insertion methodology as key synthetic steps in the formation of these biological targets. This work was conducted in collaboration with Prof. Dr. Christa Müller and Prof. Jan Balzarini. The fourth chapter explores in detail synthetic challenges in the copper-catalysed asymmetric sulfur oxidation of aryl benzyl sulfides. Significant attention is afforded to the concept of self-disproportionation of enantiomers (SDE), an underappreciated phenomenon despite being known in the literature, but also to the observation of localised partitioning of enantiomers in the solid state even in the absence of SDE, which can lead to erroneous determination of enantiopurity. Each of chapters 2–4 is concluded with the associated experimental details, including spectroscopic and analytical data, for compounds synthesised during this work.