A novel synthetic route for the preparation of Pomalyst® and analogues from biomass by milling and extruder

Herein, we describe the first preparation of the drug Pomalyst and analogues from renewable starting materials in two steps by ball milling. The operationally simple procedure requires the use of a N-Boc substituted furan, obtained from lignocellulosic biomass, maleimides, sodium chloride and sodium carbonate. The methodology was employed to prepare a library of fluorescent phthalimides with modest to excellent efficiency (50-87%) by a sequential two-step milling process featuring a Diels–Alder reaction followed by aromatisation. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs), as well as to the gram-scale synthesis of APIs (compound 8) by extruder, all in the absence of a reaction solvent.