Synthesis, structure, and reactivity of Omeprazole and related compounds

This thesis is concerned with the synthesis and properties of racemic and enantiopure sulfoxides, compounds which have application as biologically active agents and are useful tools for chemical synthesis. Particular focus is placed on the sulfoxide Omeprazole, which is one of the world’s best selling pharmaceutical products, and the single isomer form of the drug (S)-Esomeprazole. Chapter one covers the fundamental aspects of sulfoxide chemistry, the synthesis of racemic sulfoxides, and describes various approaches to the production of chiral sulfoxides in optically pure form such as resolution, nucleophilic substitutions methodologies, and non-metal based oxidative processes which use either chiral catalysts or chiral oxidants. Chapter two continues this review discussing stereoselective sulfide oxidations using metal catalysts. The discovery, mechanism of action, and large scale synthesis of Omeprazole, a biologically active sulfoxide used to treat ailments associated with excess stomach acid, is discussed in chapter three. In addition, this chapter examines the developments of the single enantiomer drug (S)-Esomeprazole and the various synthetic strategies employed in the production of this chiral sulfoxide. The ensuing chapters describe my own work: chapter four contains work on the synthesis of a range of sulfides, racemic sulfoxides, and sulfones. Following on from this the asymmetric synthesis of chiral sulfoxides, including (S)-Esomeprazole, using a modified Kagan type titanium tartrate catalyst system was investigated with the achievement of sulfoxidation enantioselectivities of up to > 99.5% ee. In chapter five the development of a new method for the determination of enantiomeric excess of (S)-Esomeprazole by 1H NMR is examined. Chiral tartrates were employed as chiral shift agents (CSA) and were found to provide efficient and accurate measurement of sulfoxide ee. The choice of NMR solvent, the host:guest ratio, and the efficacy of the tartrates to act as CSA for a range of structurally diverse sulfoxides was also investigated. Chapter six covers three studies on the structures and reactivities of Omeprazole and related sulfoxides. X-ray crystallographic diffraction (XRD) was employed to investigate the solid state structures and packing a range of sulfoxides. The effect of annular tautomerism was explored by 1H and 13C NMR for a series of benzimidazole based sulfoxide species, including Omeprazole. Finally, 1H NMR was employed to investigate the selective deuteration of sulfoxides such as Omeprazole, including the examination of H/D-exchange observed by NMR in DMSO-d6.