|Credit: OPRD, Turconi et al.|
The utility of the Aubry reaction allows the generation of singlet oxygen, and thus the Schenck ene reaction, while avoiding the need for photochemical equipment. While in principle highly attractive, photochemical reactions are rarely practiced in industry25 and there is even less precedence for the large-scale application of the Schenck ene reaction with photochemically generated singlet oxygen.
This is easily understood, as the hurdles to the implementation of a large-scale Schenck ene reaction are significant. Apart from the lack of experience and equipment, the choice of permissible solvents is very limited, the resulting products are inherently unsafe hydroperoxides, and the chemical engineering aspects such as mixing, gas transfer, and light transmission are unusually complex on scale.More on the chemical engineering challenges:
On the basis of these results, a dedicated pilot unit was set up at Sanofi facility, Neuville (France). We selected a semibatch mode concept with a recirculation loop, which is possible as artemisinin is very stable under the reaction conditions and it offers optimal conditions versus energy consumption and the transformation rate.
In addition to the other chemical engineering challenges, critical parameters included construction materials that minimize the loss of light (optimizing the quantum photonic yield) and the choice of a lamp with the optimal spectral distribution of emitted spectrum (medium pressure mercury/gallium lamp). The unit must also ensure a good turbulence of the recirculating fluid and allow a good gas−liquid transfer, while maintaining the internal temperature at −10 °C.The first batch was piloted at 50 kg scale and now they're expected to run 60 tons a year, at a 370 kg batch size. That's 162 batches (?), which indicates a pretty impressive cycle time, although these numbers tend to get fuzzy around the edges (i.e. assuming running the plant at 100% capacity, which may not happen, etc.)
Of course, you have to read the Experimental Section* to get the full flavor of this:
Step 3: Photooxidation of Mixed Anhydride (DHAEMC) to Artemisinin. To the solution of DHAEMC (CJ's note: they started with 600 kg of artemisinic acid, 2 steps previous) were added 2570 kg dichloromethane and 300 g tetraphenylporphyrin (TPP) before the solution was exposed to light irradiation using photoreactors containing mercury vapour lamps and ambient air bubbling at about −10 to −15 °C. In the beginning of the irradiation 132 kg trifluoroacetic acid was added to the reaction mixture. The reaction was monitored by HPLC. As soon as the reaction was completed, the solution was treated twice with 720 L aqueous solution of sodium bicarbonate and was subsequently washed with 1440 kg water. The washed organic phase was treated with 30 kg activated charcoal and filtered. Before the crystallisation step,I don't have the professional capacity to comment on this intelligently, other than to say that it's a really impressive feat, in my opinion. I think it's apparent that the Sanofi coworkers not only had to design (and did!) robust enough chemistry to get it done, they had to design reactors to make this happen. Finally, it should be noted that Sanofi-Aventis was working with the Gates Foundation under a "no profit, no loss" model for anti-malarials. This seems like a pretty clear example of the good that industrial chemistry can do.
the ADT24h of the reaction mixture was checked.
1. Turconi, J.; Griolet, F.; Guevel, R.; Oddon, G.; Villa, R.; Geatti, A.; Hvala, M.; Rossen, K.; Göller, R.; Burgard, A. "Semisynthetic Artemisinin, the Chemical Path to Industrial Production." Org. Process. Res. Dev. ASAP DOI: 10.1021/op4003196
*OPRD's experimental sections are the best, because it's always "To the reactor was added 14 quintillion liters of solvent..."