Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives

A method for reducing artemisinin in a continuous manner comprising:

• 1) providing a column containing a hydride reducing agent, at least one activator and at least one solid base or providing a first column containing at least one solid base and a second column containing a hydride reducing agent and at least one activator,
• 2) providing a continuous flow of a solution of artemisinin in at least one aprotic solvent containing at least one C1-C5 alcohol through the column containing the hydride reducing agent, the at least one activator and the at least one solid base or through the first column containing the at least one solid base and the second column containing the hydride reducing agent and the at least one activator,
• 3) thereby reducing artemisinin in a continuous manner to dihydroartemisinin of the following formula
• wherein
• the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, potassium borohydride, calcium borohydride, Superhydride® (a solution of lithium triethylborohydride), L/K/N-Selectrides (lithium/potassium/sodium tri(sec-butyl) borohdyride), LiAlH(OtBu)3, RedAl, DIBAL-H, Titanocene and a mixture thereof;
• the at least one activator is selected from the group consisting of alkaline metal halides, alkaline earth metal halides, In salts, I2, Ni salts, Ni foam, hydrogels containing Co and/or Ni nanoparticles, nanotubes containing Au nanoparticles, Pb salts, TiO2 containing Pd or Co—Ni—P, polyaniline salts, propanephosphonic acid cyclic anhydride, protein-capped Au nanoparticles, pyridinium based dicationic ionic salts, Ru salts, Ru immobilized on Al2O3 pellets, Ru-activated carbon, CeCl3, Ru—CeO2, Ru—TiO2, Ru-γ Al2O3, Ru60Co20Fe20, Ru-promoted sulphated zirconia, titanyl acetylacetonate, Au nanoparticles, Co salts, Celite® Amberlyst 15, Amberlyst 15 with dextrose or galactose and phloroglucinol;
• the at least one solid base is selected from the group consisting of:
• metal hydroxides, metal carbonates, ammonium hydroxide, and tetraalkylammonium hydroxides;
• and
• the at least one C1-C5 alcohol is selected from the group consisting of:
• CH3OH, CH3CH2OH, CH3CH2CH2OH, CH3CH2CH2CH2OH, CH(CH3)2CH2OH, CH3CH2CH2CH2CH2OH, HOCH2CH2OH, HOCH2CH2CH2OH, HOCH2CH2CH2CH2OH, HOCH2CH2CH2CH2CH2OH, HOCH2CH(OH)CH2OH, HOCH2CH(OH)CH2CH2OH, HOCH2CH(OH)CH(OH)CH3, HOCH2CH(OH)CH(OH)CH2OH, HOCH2CH(OH)CH2CH2CH2OH, HOCH2CH2CH(OH)CH2CH2OH, HOCH2CH(OH)CH(OH)CH2CH2OH, HOCH2CH(OH)CH2CH(OH)CH2OH, HOCH2CH(OH)CH(OH)CH(OH)CH2OH, HC(CH2OH)3, HO—C(CH2OH)3, and C(CH2OH)4.