This chapter focuses on the synthesis of phosphonates relevant for pharmaceutical
applications due to their real or potential biological activity. The classes of compounds
discussed embrace α-hydroxyphosphonates, methylenebisphosphonates, and dronic acid
derivatives. The latter species are useful in the treatment of illnesses including
osteoporosis or cancer diseases. The Pudovik reaction is the most common method for
the synthesis of α-hydroxyphosphonates. Another pathway for their synthesis is the
Abramov reaction. In addition, hydroxyphosphonates may be prepared from α-oxophosphonates
by reaction with Grignard reagents, or by the oxidation of alkylphosphonates. Additional
potentially bioactive compounds may be obtained by the modification of hydroxyphosphonates
by acylation, alkylation, nucleophilic substitution, oxidation, rearrangement and
hydrolysis. Hydroxy-methylenebisphosphonates may be obtained by the addition reaction
of dialkyl phosphites or diarylphosphine oxides to the C=O group of the α-oxophosphonates.
Base catalysts, for example, dialkylamines are applied in this reaction. Using less
catalyst at a lower temperature, the adduct is the major component, while using more
catalyst at a higher temperature, the rearranged product predominates. The outcome
may also be influenced by the substitution pattern. Dronic acids are usually prepared
from the corresponding carboxylic acid derivative using various phosphorus reagents,
such as phosphorus trichloride and phosphorous acid. Methanesulfonic acid (MSA) and
sulfolane are the most often used solvents. When using MSA, there is a need only for
phosphorus trichloride. On the one hand, it forms a mixed anhydride with the carboxylic
acid, on the other hand, it may form an even more active phosphorus reagent in reaction
with phosphorus trichloride. In sulfolane, both phosphorus trichloride and phosphorous
acid are needed. Phosphorus trichloride reacts with a carboxylic acid to form an acid
chloride, and also forms a dimer or a trimer condensate with phosphorous acid. These
species react with either the acid chloride or the carboxylic acid, leading to the
formation of ketophosphonic acid, which is further transformed via intermediate steps
to establish the dronic acid.
