Water and carbon dioxide for sustainable synthesis and separation of pharmaceutical intermediates
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The research projects presented in this thesis are mainly focused toward green chemistry and engineering: developing innovative strategies to minimize waste, improve process efficiency and reduce energy consumption. Specifically, the work was centered on the design and applications of green solvents and processes for the sustainable production of pharmaceuticals. The first project was focused on the use of CO₂ to enhance Suzuki coupling reactions of substrates containing unprotected primary amines. This work established that exceptionally challenging substrates like halogenated amino pyridines (i.e. 4-amino-2-bromopyridine and 4-amino-2-chloropyridine) are suitable substrates for Suzuki coupling reactions under standard conditions using CO₂ pressures, without the need for protection/deprotection steps which are traditionally considered to be necessary for these reactions to proceed cleanly. The second project explored the use of water at elevated temperatures (WET) for the sustainable and selective removal of protecting groups. The favorable changes that occur in the physiochemical properties (i.e. density, dielectric constant and ionization constant) of water at elevated temperatures and pressures make it an attractive solvent for the development of sustainable, environmentally green processes for the removal of protecting groups. The water-mediated selective removal of protecting groups such as N-Boc, N-Acetyl and O-Acetyl from a range of organic model compounds was successfully achieved by tuning the temperature (125 to 275°C) or properties of water. The third project investigated the use of Organic-Aqueous Tunable Solvents (OATS) for the rhodium catalyzed hydroformylation of p-methylstyrene. This enables the reactions to be carried out efficiently under homogeneous conditions, followed by a carbon dioxide (CO₂) induced heterogeneous separation. Modest pressures of CO₂ induced the aqueous-rich phase (containing the catalyst) to separate from the organic-rich phase (containing the reactant), thus enabled an easy separation and recycling of catalyst. The use of Al(OtBu)₃ as a potent catalyst toward continuous Meerwein-Ponndorf-Verley (MPV) reductions was established in the fourth project. The MPV reduction of model compounds like benzaldehyde and acetophenone to their corresponding alcohols was investigated in continuous mode as a function of temperature and catalyst loading. These results established a roadmap for the pharmaceutical industry to document the implementation of continuous flow processes in their manufacturing operations.