Greener approaches for chemical synthesis – ball mill and microwave assisted synthesis of fluoxetine and duloxetine and enantioselective catalysed addition of organometallic reagents to aldehydes

Mestres, Ricard Sola (2017) Greener approaches for chemical synthesis – ball mill and microwave assisted synthesis of fluoxetine and duloxetine and enantioselective catalysed addition of organometallic reagents to aldehydes. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

This PhD thesis focuses on the development of “greener” synthetic methodologies in organic synthesis. Turning chemical production into a more sustainable industry - by reducing the waste generated and the electricity consumption - is highly desired in a world with limited resources and increasing population. This thesis, in particular, focuses on three of the ‘12 Principles of Green Chemistry’, reducing the amount of solvent and energy consumption in a chemical process, and the use of catalytic reagents instead of stoichiometric. In the first chapter of this thesis, a greener synthetic route for the preparation of the antidepressant fluoxetine (Prozac) was developed. The use of ball milling allowed a decrease of the solvent used in the process, furthermore, microwave assisted heating provided a more efficient method compared to the traditional heating using an oil bath. Fluoxetine was synthesised with 47% yield through two different synthetic routes (3 and 4 steps respectively). In addition, the scope of the developed methodologies was tested by the attempted synthesis of the antidepressant duloxetine. The second chapter of this thesis focuses on the catalytic enantioselective synthesis of chiral alcohols. More specifically, two different methodologies for the catalytic enantioselective addition of organolithium reagents to aldehydes were successfully developed, achieving excellent yields and enantioselectivities. Furthermore, a new methodology for the use of organozirconium reagents as nucleophiles in the catalytic enantioselective 1,2-addition of alkenes to aldehydes was also developed. Last, the implementation of a catalytic enantioselective step to the previous syntheses of fluoxetine was attempted.