Continuous Flow Reduction of Artemisinic Acid Utilizing Multi‐Injection Strategies—Closing the Gap Towards a Fully Continuous Synthesis of Antimalarial Drugs

Abstract

One of the rare alternative reagents for the reduction of carbon-carbon double bonds is diimide (HN=NH), which can be generated in situ from hydrazine hydrate (N2H4⋅H2O) and O2. Although this selective method is extremely clean and powerful, it is rarely used, as the rate-determining oxidation of hydrazine in the absence of a catalyst is relatively slow using conventional batch protocols. A continuous high-temperature/high-pressure methodology dramatically enhances the initial oxidation step, at the same time allowing for a safe and scalable processing of the hazardous reaction mixture. Simple alkenes can be selectively reduced within 10-20 min at 100-120 °C and 20 bar O2 pressure. The development of a multi-injection reactor platform for the periodic addition of N2H4⋅H2O enables the reduction of less reactive olefins even at lower reaction temperatures. This concept was utilized for the highly selective reduction of artemisinic acid to dihydroartemisinic acid, the precursor molecule for the semisynthesis of the antimalarial drug artemisinin. The industrially relevant reduction was achieved by using four consecutive liquid feeds (of N2H4⋅H2O) and residence time units resulting in a highly selective reduction within approximately 40 min at 60 °C and 20 bar O2 pressure, providing dihydroartemisinic acid in ≥93% yield and ≥95% selectivity.

Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry

“…The continuous production of active ingredients for artemisin-based antimalarial drugs was compared with batch systems [156]. Multiple N2H2 feeds improved selectivity and allowed milder reduction conditions with respect to batch processes using H2.…”

Aerobic Oxidations in Continuous Flow

“…Since the initial oxidation step is rather slow under laboratory batch conditions, catalysts are usually added in order to provide a feasible experimental protocol. Kappe and coworkers could show that a continuous flow protocol in a high-temperature/highpressure regime significantly enhances this process and thus eliminates the need for a catalyst [139,140]. In the original procedure, an organic stream consisting of an olefin and hydrazine hydrate in n-propanol was mixed with oxygen resulting in a segmented flow pattern which is heated in a residence time unit to 100-120 C at a back pressure of 20 bar [139].…”

“…By studying the hydrazine oxidation in more detail, the authors developed a strategy for more challenging substrates such as artemisinic acid (23) to obtain the direct precursor molecule (24) of the anti-malaria drug artemisinin (Scheme 19) [140].…”

“…In the previous chapter, the reduction of artemisinic acid (23) to dihydroartemisinic acid (24) utilizing O 2 and hydrazine was already discussed [140]. The reduced compound (24) .…”

Continuous flow synthesis of antimalarials: opportunities for distributed autonomous chemical manufacturing

“…23 They report the chemo-and diastereoselective reduction of the alkene of the vinylogous acid with a high yield using a diimide reduction. This process avoids the use of catalysts, allowing for simple reaction workup, with side products being water and nitrogen gas.…”