Pilot Plant PAT Approach for the Diastereoselective Diimide Reduction of Artemisinic Acid

Abstract

In this study, an attractive route for the diastereoselective synthesis of dihydroartemisinic acid (DHAA) starting from artemisinic acid (AA) is presented. Diimide was used as a reducing agent, which was generated by two different methods: (1) by the reaction of hydrazine monohydrate and hydrogen peroxide and (2) by the reaction of hydrazine monohydrate and oxygen. Both methods were found to be suitable for the diimide reduction of AA showing full conversion and a high diastereoselectivity. Due to advantages in the crystallization step of DHAA, the second option for generation of diimide was chosen for the pilot plant scale-up. The reaction and the crystallization process development as well as the batch production in the pilot plant were monitored and controlled using dispersive Raman spectroscopy as PAT tool. Three DHAA batches in kilogram scale were successfully produced by the reaction of artemisininic acid, hydrazine monohydrate, and a gas mixture of nitrogen and oxygen (containing 5% v/v oxygen) in 2-propanol at 40 °C. Excellent yields of >90% (including the crystallization, isolation, and drying step) as well as high diastereoselectivities (≥97:3) of the products were achieved by the elaborated pilot plant manufacturing processes.

Applying green chemistry to the photochemical route to artemisinin

“…50% were obtained (entries 3 & 4), comparable to published routes. 9,13 Most yields were measured directly from NMR of the product solution but some samples of 1 were isolated and more fully characterized by a variety of techniques including NMR, melting point and optical rotation; the data are in excellent agreement with those recorded from an authentic sample of 1 from the commercial process (see ESI).…”

“…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.…”

Aerobic Oxidations in Continuous Flow

“…In addition, the temperature could be reduced to 60 C in order to obtain high selectivity and diastereomeric ratio. Notably, a comparison with the catalyst-free batch reduction of the same compound at 40 C demonstrated significantly longer reaction times (11 h) in order to obtain similar values for isolated yield and product purity [141].…”

Ethnochemistry and Human Rights

“…For example, traditional knowledge is often a starting point in drug discovery [3], including: aspirin and codeine (pain treatment); quinine (treatment of malaria); pilocarpine (treatment of glaucoma), and Sangre de Grado (treatment of diarrhea). The plant Artemisia annua has been used for over two thousand years in Chinese traditional medicine for its antimalarial properties; the active agent is artemisin and is used today on large scales [4]. Several thousands of natural products and mixtures are currently used in medicine with origins from European, Asiatic, and American Indian healers [5] [6].…”