Synthesis of Symmetrical Methylenebis(Alkyl Hydrogen Phosphonates) by Selective Cleavage of Methylenebis(Dialkyl Phosphonates) with Morpholine

Abstract

The preparation of partial esters of methylenebisphosphonic acids has been of recent interest due to their potential therapeutic applications. This paper describes a convenient method to prepare symmetrical methylenebis(alkyl hydrogen phosphonates) by the selective cleavage of the corresponding methylenebis(dialkyl phosphonate) with refluxing morpholine. The effects of structural variations on the amine as well as the substrate have been investigated to understand the scope and limitations of this reaction. A superior approach to hindered bisphosphonic acid esters involves the cleavage of their dimethyl esters, 4, using morpholine. This method is also useful to access a number of C-alkyl dialkyl methylenebisphosphonic acids such as 6. This study clearly shows that cleavage with morpholine is convenient, inexpensive, and allows for the preparation of a variety of P,P′-disubstituted partial esters in good yields and high purity.

Keywords:

• Bisphosphonic acids
• Metal ion extractants
• Bone disease

Acknowledgments

This work was funded by the Environmental Management Sciences Program of the Offices of Science and Environmental Management, U.S. Department of Energy, under grant numbers 991172402 (NMSU) and DE-FGO7-98ER14928 (LUC) and contract number W-31-109-ENG-38 (ANL). We would also like to acknowledge financial support from the National Institutes of Health under PHS Grant No. SO6 GM08136 (NMSU). We thank Mr. Dickie Romero (NMSU), Mr. James Allen (NMSU) and Mr. Peter R. Zalupski (LUC) for technical assistance.