Homogeneous hydrogenation and photochemistry as tools in pharmaceutical process development

Ruthenium catalysed ester reductions using hydrogen have become increasingly industrially relevant as a means of accessing primary alcohols, while avoiding the need for pyrophoric and wasteful metal hydride-based reducing agents. A catalytic system was identified capable of reducing esters under mild conditions accessible in general purpose pressure vessels more likely encountered within the pharmaceutical industry (< 10 bar of hydrogen pressure). Process understanding was obtained using an experimental design approach which was used to rationalise and suppress the formation of impurities. Mechanistic insight was also gathered using time-course experimentation and in situ monitoring. A number of substrates, more representative of the types of molecules encountered in a pharmaceutical environment were tested in the reaction. Selected substrates were scaled-up in batch and in a bespoke CSTR flow reactor to furnish relevant pharmaceutical intermediates. These processes compared favourably to existing metal hydride mediated processes, both in the reduction of waste and number of unit operations. The resulting alcohols were then further elaborated to generate more advanced intermediates. Photochemical transformations are another increasingly useful technology being employed within the pharmaceutical industry as a tool to enable novel disconnections, though these can be challenging to scale. The second part of this thesis examines the photochemical bromination of two substrates. Further optimisations are performed on the benzylic bromination of ethyl 4-methylbenzoate to intensify the process. Simplification of the work-up and isolation procedures compared to a previous process were also studied. Scale-up was performed in a plug-flow reactor as well as a prototype photochemical DART flow reactor. The results from this experimentation have been used to inform the design of a next-generation prototype reactor.Ruthenium catalysed ester reductions using hydrogen have become increasingly industrially relevant as a means of accessing primary alcohols, while avoiding the need for pyrophoric and wasteful metal hydride-based reducing agents. A catalytic system was identified capable of reducing esters under mild conditions accessible in general purpose pressure vessels more likely encountered within the pharmaceutical industry (< 10 bar of hydrogen pressure). Process understanding was obtained using an experimental design approach which was used to rationalise and suppress the formation of impurities. Mechanistic insight was also gathered using time-course experimentation and in situ monitoring. A number of substrates, more representative of the types of molecules encountered in a pharmaceutical environment were tested in the reaction. Selected substrates were scaled-up in batch and in a bespoke CSTR flow reactor to furnish relevant pharmaceutical intermediates. These processes compared favourably to existing metal hydride mediated processes, both in the reduction of waste and number of unit operations. The resulting alcohols were then further elaborated to generate more advanced intermediates. Photochemical transformations are another increasingly useful technology being employed within the pharmaceutical industry as a tool to enable novel disconnections, though these can be challenging to scale. The second part of this thesis examines the photochemical bromination of two substrates. Further optimisations are performed on the benzylic bromination of ethyl 4-methylbenzoate to intensify the process. Simplification of the work-up and isolation procedures compared to a previous process were also studied. Scale-up was performed in a plug-flow reactor as well as a prototype photochemical DART flow reactor. The results from this experimentation have been used to inform the design of a next-generation prototype reactor