Continuous synthesis of artemisinin-derived medicines

Abstract

Described is a continuous, divergent synthesis system which is coupled to continuous purification and is capable of producing four anti-malarial APIs. The system is comprised of three linked reaction modules for photooxidation/cyclization, reduction, and derivatization. A fourth module couples the crude reaction stream with continuous purification to yield pure API.

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…[55][56][57] Using a photochemical reactor, an unconventional route could be developed to Ibuprofen via a photo-Favorskii rearrangement. 58 Continuous flow electrochemistry was used as an enabling technology in the synthesis of the indole alkaloid Nazlinine and its analogues.…”

“…57 Modification of the processing parameters may also be necessary, when long term operation is desired. The opening Knoevenagel addition step of the synthesis of a Nevirapine precursor could be efficiently conducted on a solid basic Al 2 O 3 .…”

“…25 These efforts are exemplified by the production of Artemisinin related APIs, where monitoring of the reaction stream after a photochemical transformation could reveal an eventual lamp failure. 57 …”

“…A continuous three-stage purification method was developed for a-artesunate, consisting of precipitation and filtration of by-products, followed by chromatography in a multi-column arrangement and finally crystallization of the product. 57 In a more recent study, a closely related system was constructed, based on continuously operated simulated moving bed (SMB) chromatography (Fig. 19).…”

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

“…After a residence time of approximately 20 minutes, the output was stirred at room temperature for 24 Seeberger and co-workers further extended their work to incorporate multistep processing, whereby the initial photochemical process was telescoped into reduction and derivatisation steps to deliver artemisinin derived products. 31 Key to the success was the productive merging of the individual steps. In this regard the photosensitizer 9,10-dicyanoanthracene (DCA) was combined with a stream of oxygen and passed through the photoreactor (Scheme 6).…”