Hydrophobic vs. hydrophilic ionic liquid separations strategies in support of continuous pharmaceutical manufacturing

Abstract

Taking advantage of the dramatically different solvent properties of hydrophilic ionic liquids (ILs) when dry vs. when wet allows unique separations strategies compared to the use of hydrophobic ionic liquids. This is demonstrated here by comparing the separation of a water insoluble amide intermediate for aliskiren from its reactants, a water insoluble lactone, water soluble 3-amino-2,2-dimethylpropanamide, and the water soluble promoter 2-ethylhexanoic acid, using the hydrophobic ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C₂mim][NTf₂]) and the hydrophilic ionic liquid 1-ethyl-3-methylimidazolium acetate ([C₂mim][OAc]). Both the water soluble [C₂mim][OAc], when dry, and water insoluble [C₂mim][NTf₂] can dissolve the highly hydrophobic and hydrophilic compounds simultaneously, but the two ILs require different strategies to separate the mixtures of these compounds. Using the hydrophobic [C₂mim][NTf₂], the hydrophobic compounds can be separated from the hydrophilic reactants by extraction and precipitation with water, however, the hydrophobic IL is more difficult to completely remove after the separations. In [C₂mim][OAc], the most hydrophobic starting material can be extracted from the IL phase into ethyl acetate, and then water can be added to precipitate the hydrophobic amide product while at the same time removing the IL from the pharmaceuticals.