Facile N-alkylation of acridine esters with 1,3-propane sultone in ionic liquids

Abstract

Hydrophilic chemiluminescent acridinium esters containing N-sulfopropyl groups are extremely useful labels in the clinical diagnostics industry. The synthesis of these labels is normally accomplished by N-alkylation of the acridine ester precursors with the carcinogenic reagent 1,3-propane sultone in neat reactions where the alkylating reagent also serves as the solvent. Product yields are often poor, the reactions are not reproducible and are also difficult to scale-up. In our efforts to develop a greener and a more efficient synthesis of N-sulfopropyl acridinium esters, we have discovered that commonly used room temperature ionic liquids such as [BMIM][BF4] and [BMIM][PF6] are excellent media for the N-alkylation of poorly reactive acridine esters with 1,3-propane sultone. Advantages include a significant reduction in the amount of toxic 1,3-propane sultone needed for good conversion to product, and minimal formation of polysulfonated products. The alkylation reaction in ionic liquids is amenable to scale-up for the synthesis of gram quantities of hydrophilic, chemiluminescent acridinium esters.