The synthesis of 1-amino-2-hydroxy- and 2-amino-1-hydroxy-substituted ethylene-1,1-bisphosphonic acids and their N-methylated derivatives

Abstract

A synthesis of 2-amino-1-hydroxyethylene-1,1-bisphosphonic acid 3 has been developed from N-phthaloylglycine via dimethyl 2-( N-phthaloylamino)acetylphosphonate 1. The preparation of the N-methylated and N, N-dimethylated derivatives 4 and 5 has been achieved by the reaction of 3 with formic acid and formaldehyde. The synthesis of 1-amino-2-hydroxyethylene-1,1-bisphosphonic acid 9 (RR′H) and its N-methylated and N, N-dimethylated analogues has been achieved by the reaction of phosphorus trichloride and phosphorous acid with the appropriate O-benzyl protected hydroxyacetamide, followed by catalytic hydrogenolysis of the protecting group.