Flow chemistry in application to the multi-step synthesis of donepezil and Suzuki-Miyaura coupling reactions

Abstract

In recent years, interest and research in flow chemistry where reactions occur in a continuous manner has grown at a rapid rate. This type of chemistry now offers fully automated processes with increased safety and efficiency and is commonly associated with improved yields and reduced reaction times. In this dissertation, we focus on the development of more economical, greener, and safer process routes to various organic molecules by translating batch reactions into flow processes. As an application, we used flow chemistry to synthesize, 1) an anti-Alzheimer’s disease agent donepezil and 2) to conduct Suzuki-Miyaura coupling reactions between various aryl diazonium tetrafluoroborate salts and phenyl boronic acid. Our medicinal chemistry research group has been involved with the identification of neuroprotective agents based-upon the chemical space surrounding the acetylcholinesterase inhibitor donepezil. As such, the development of a flow-based process route to produce donepezil was of interest to us. In batch, donepezil is synthesized via a five-stage process involving a 1) benzylation, 2) reduction, 3) oxidation, 4) aldol condensation and 5) hydrogenation. We translated the five-stage process into a four-stage continuous flow process by substituting the two-step reduction/oxidation with a selective reduction diisobutylaluminium hydride, leading to a conversion of 78% to the aldehyde product in just 15 minutes compared to the 90 minutes it took under batch conditions with a conversion of 93%. The final stage, hydrogenation, suffers from selectivity issues as some debenzylation occurs when the benzylated alkene precursor undergoes reduction. As such, we conducted the reaction in a recycling loop with catalytic 10% Pd/C and hydrogen gas resulting in a conversion of 82% in 73 minutes in flow conditions compared to the 150 minutes it took in batch to give 87% conversion. Aryl diazonium tetrafluoroborate salts have a broad spectrum of reactivity and their high reactivity makes them very good coupling partners in the Suzuki-Miyaura reactions, despite this, only a few publications have been documented due to issues surrounding the safe handling of the salts. We envisaged using flow chemistry and its associated advantage for conducting exothermic reactions in a safer manner for the correct handling and subsequent use of these salts in the cross couplings. The initial reaction is the diazotization reaction of various aniline derivates with isopentyl nitrite in the presence of tetrafluoroboronic acid to form the salts with yields in the range 89 – 100% after 15 minutes residence time in flow and 30 minutes reaction time in batch chemistry. The synthesized salts were used in the cross-coupling to form biphenyls, in batch, the reaction yields were relatively low ranging from 32 – 60% after 2 hours while under flow conditions yields of 60% could be achieved in a significantly reduced residence times of less than 5 minutes.