|As reported back in 2012 here chemical company Sanofi and the Bill and Melinda Gates Foundation have joined forces (Sanofi the know-how and Bill the money) to increase production of the important antimalarial drug artemisinin. In a recent OPRD publication Sanofi chemists present a commercial-scale (no-loss no profit) production line with a capacity of 60 tonnes, starting from yeast-produced artemisinic acid. Here is the summary. |
In step one from artemisinic acid to dihydroartemisinic acid (a dehydrogenation) the Wilkinson catalyst was deemed too expensive and replaced by ruthenium chloride (R)-DTBM-Segphis (a modified segphos). Scale: 600 Kg, 90% diastereoselectivity. The compound was next activated with ethylchloroformate and potassium carbonate in dichloromethane to the anhydride. The photochemical step consisted of adding tetraphenylporphyrin as a sensitizer and trifluoroacetic acid in dichloromethane. The subsequent Schenck ene reaction / Hock rearrangement requires two equivalents of singlet oxygen. Where the prior art yielded 41% of product, this photochemical solution pushes out 55%. Side note: the article does not really explain why the acid was activated, the Seeberger procedure does not include this step. Remaining challenge: product isolation was accomplished by simultaneous DCM distillation - solvent replacement with n-heptane and crystallisation. Pretty amazing when considering this is still industrial production at the hundreds of kilogram scale and the final product is a labile peroxide!
Please do admire the photochemical reactor pic embedded in the article. At the Sanofi plant in Garessio (Italy) it is Christmas every day of the year.