An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part I

Abstract

Artemisinin and its derivatives, such as artemether, are highly sensitive compounds, which require careful optimized production processes for their manufacture. Due to robustness issues, the manufacturing procedure of the reduction of artemisinin with potassium borohydride to dihydroartemisinin was reinvestigated. The most important factor for obtaining optimal yields is to ensure low levels of contamination of potassium hydroxide in potassium borohydride. Application of a lower reaction temperature, fast addition rate of potassium borohydride, and careful control of the pH during the quench with acid are further important parameters in guaranteeing a robust process. In the redesign of the conversion of dihydroartemisinin to artemether, the yield was increased, and dichloromethane was replaced by the ecologically friendlier methyl acetate. A robust manufacturing process for artemether is now at hand, allowing the production of this important medicine reliably and in good quality and yield.

A simplified and scalable synthesis of artesunate

“…After destroying the excess of NaBH 4 with acetic or hydrochloric acid, DHA is usually precipitated by the addition of water. Through this procedure, DHA could be obtained in satisfactory yields (79–89%) as published previously [16, 19, 21]. In an alternative strategy, the yield of DHA could be further enhanced by neutralization with 30% acetic acid/MeOH at 0–5 °C, concentration, and multiple extraction of the white residue using Et-OAc.…”

“…The transformation of artemisinin into artesunate was commonly realized by a two-step process involving the reduction with NaBH 4 [15–19], KBH 4 [20, 21] or diisobutylaluminium hydride (DIBAL) [22, 23], followed by esterification using succinic anhydride [24, 25]. However, these syntheses described in the scientific literature are not suitable for an industrial large-scale process because they require very low temperature, highly expensive or toxic reagents and solvents or provide only moderate yields.…”

“…As a consequence of the competing methanol-induced solvolysis, a certain excess of the reagent is definitely required. It is known that the instability of NaBH 4 in MeOH can be overcome by the addition of a base [34], but the extreme vulnerability of DHA towards small amounts of strong bases [21] excludes this approach. Apparently, the application of a lower reaction temperature leads to a slower decomposition of NaBH 4 by MeOH [21].…”

“…It is known that the instability of NaBH 4 in MeOH can be overcome by the addition of a base [34], but the extreme vulnerability of DHA towards small amounts of strong bases [21] excludes this approach. Apparently, the application of a lower reaction temperature leads to a slower decomposition of NaBH 4 by MeOH [21]. As a consequence, the reaction time has to be kept short, and the reaction temperature kept as low as possible.…”

New Method for the Synthesis of Ether Derivatives of Artemisinin

“…The ether derivatives of artemisinin are usually synthesized from dihydroartemisinin 2 by reaction with the desired alcohol in the presence of acid catalysts such as HCl, [7] para-toluenesulfonic acid (PTSA), [8] BF 3 Á Et 2 O, [9] or Me 3 SiCl, [10] but all these catalysts have very long reaction times and require aqueous workup. BF 3 Á Et 2 O [9] or Me 3 SiCl [10] has the additional drawback of moisture sensitivity.…”