Collect. Czech. Chem. Commun. 1995, 60, 670-680

Synthesis of 3-(4-Pyridinyl)-, 3-(2-Chloro-4-pyridinyl)- and 3-(2-Amino-4-pyridinyl)propoxymethanephosphonic Acid

Marcela Krečmerová, Antonín Holý and Milena Masojídková

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic


Reaction of sodium salt of 4-(3-hydroxypropyl)pyridine (I) with diisopropyl p-toluenesulfonyloxymethanephosphonate (II) afforded diisopropyl ester of the corresponding phosphonomethyl derivative (III), together with 4-cyclopropylpyridine (IV). The ester III was converted into free 3-(4-pyridinyl)propoxymethanephosphonic acid (V). The synthesis of 3-(2-amino-4-pyridinyl)propoxymethanephosphonic acid (XVI) started from 4-(3-benzoyloxypropyl)pyridine (VII) via the N-oxide VIII which on heating with phosphoryl chloride afforded the 2-chloro derivative IX. Compound IX was debenzoylated with sodium methoxide to give 2-chloro-4-(3-hydroxypropyl)pyridine (XI). Condensation of sodium salt of XI with tosylate II afforded diisopropyl 3-(2-chloro-4-pyridinyl)propoxymethanephosphonate (XIII) and 2-chloro-4-cyclopropylpyridine (XIV). Deprotection of the ester groups in XIII with bromotrimethylsilane gave 3-(2-chloro-4-pyridinyl)propoxymethanephosphonic acid (XV). The chlorine atom in position 2 was replaced by reaction of compound XV with aqueous ammonia at 200 °C under catalysis with copper(II) sulfate. This gave 3-(2-amino-4-pyridinyl)propoxymethanephosphonic acid (XVI) as the final product.