title: 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.
authors: Christian Doppler Laboratory for Flow Chemistry (CDLFC) and Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz (Austria), Fax: (+43) 316 3809840.
authors: Bartholomäus
authors: B
authors: Pieber
authors: Toma
authors: T
authors: Glasnov
authors: C Oliver
authors: CO
authors: Kappe
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry*; D037621:Artemisinins / Q000737:chemistry* / Q000627:therapeutic use; D015394:Molecular Structure
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C047721:artemisic acid
keywords: antimalarial drugs; flow chemistry; reactor design; reduction; synthetic methods