Semisynthetic Artemisinin, the Chemical Path to Industrial Production

Abstract

A new commercial-scale alternative manufacturing process to produce a complementary source of artemisinin to supplement the plant-derived supply is described by conversion of biosynthetic artemisinic acid into semisynthetic artemisinin using diastereoselective hydrogenation and photooxidation as pivotal steps. This process was accepted by Prequalification of Medicines Programme (PQP) in 2013 as a first source of nonplant-derived-artemisinin in industrial scale from Sanofi production facility in Garessio, Italy.

Porphyrins as Catalysts in Scalable Organic Reactions

“…The above mentioned method has opened perspectives to carry out the crucial step in the synthesis of artemisinin (Scheme 33) [115]. The great importance of TPP as photosensitizer for singlet oxygen production can be highlighted by the green gram-scale synthesis of artemisinin recently established as an industrial process by the pharmaceutical company Sanofi [116].…”

Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism

“…There has been much interest in determining the steps involved in the biosynthesis of artemisinin in recent years, largely driven by efforts to produce this compound through a completely biosynthetic microbial-based fermentation route (8,9). Presently microbial production is at best semisynthetic, terminating at artemisinic acid (AA), which must then be extracted from culture and chemically converted to artemisinin by using photooxidation (8,10). The lack of a low-cost, scalable conversion process is considered to be a major factor in the failure so far of the semisynthetic route to sustainably impact the market, making it uncompetitive with plant-based production (11).…”

Applying green chemistry to the photochemical route to artemisinin

“…1). [8][9][10] With the carbon skeleton already assembled, the final conversion of 3 to 1 formally requires the introduction of two O 2 molecules. In this context, photochemically generated 1 O 2 is attractive from a green chemistry point of view because (a) both of the oxygen atoms are incorporated Fig.…”

“…The current Sanofi process adds an extra activation step to form the ester of 3 (mixed anhydride) rather than the free acid. 10 Hydroperoxide 4 is converted through an acid-catalyzed ring opening process into enol 6 (6 has been observed under oxygen free conditions). This reactive intermediate is then finally oxidized into 1, a step which requires heating to room temperature and longer reaction times.…”

“…These begin with the use chlorinated solvents such as dichloromethane (DCM) for the 1 O 2 reaction; the use of the relatively toxic acid, trifluoroacetic acid (TFA); the need to carry out the photo-oxidation at low temperature (typically -20 o C) to increase selectivity towards 4; [13][14][15] and the ultimate purification of 1, involving multiple washings to remove the acid, the loss of photosensitizer and solvent exchange to allow crystallization. 10 In addition, all of these processes generate 1 in the presence of free acid which is concerning because 1 is not stable under acidic conditions 17 and this could ultimately reduce productivity.…”