Efficient Synthesis of Ibandronate in the Presence of an Ionic Liquid

Background: Ibandronate is a prominent representative of α-hydroxymethylenebisphosphonic acid (dronic acid) derivatives applied in the treatment of bone diseases. Methods: Ibandronate was synthesized from N-methyl-N-pentyl-β-alanine using phosphorus trichloride and phosphorous acid in different ratios, applying sulfolane as the solvent (1.), or under solvent-free conditions (2.), or in ionic liquids as additives (3.). Results: In the first two cases (1. and 2.), using phosphorus trichloride and phosphorous acid in molar ratios of 2:4 and 3:4, pure ibandronate was obtained in yields of 72-83%. In the presence of 10% of [bmim][BF4] as an additive (3.), a better yield of 82/90% was obtained applying ratios of 2:2 and 3:2 of the P-reagents assuming less of the phosphorous acid. Conclusion: The new methods developed mean record outcomes in respect of the valuable drug, ibandronate.