Collect. Czech. Chem. Commun. 1995, 60, 659-669

Preparation of Phosphonomethyl Ethers Derived from 2-Phenylethanol and Its Amino Derivatives

Marcela Krečmerová and Antonín Holý

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


A series of compounds derived from the acyclic nucleoside antiviral 9-(2-phosphonomethoxyethyl)adenine (PMEA), in which the adenine ring is replaced by phenyl, 4-aminophenyl, 3-aminophenyl or 3,5-diaminophenyl group, has been prepared starting from the corresponding phenethyl alcohols. 2-(3-Aminophenyl)ethanol was prepared from 3-nitrobenzoyl chloride using the Arndt-Eistert reaction. The primarily formed diazoketone Ia was converted into ethyl 3-nitrophenylacetate (IIa) which on catalytic hydrogenation afforded ethyl 3-aminophenylacetate (IIIa). Compound IIIa was reduced with lithium aluminium hydride to give 2-(3-aminophenyl)ethanol (IVa). 2-(3,5-Diaminophenyl)ethanol (IVb) was prepared analogously from 3,5-dinitrobenzoyl chloride. After protection of the amino group with dimethylaminomethylene group, the alcohol IVa was converted to diisopropyl 2-(3-aminophenyl)ethoxymethylphosphonate (XII) by reaction with sodium hydride and diisopropyl p-toluenesulfonyloxymethanephosphonate, followed by deprotection of the amino group by treatment with ammonia. Reaction of diisopropyl ester XII with bromotrimethylsilane gave free 2-(3-aminophenyl)ethoxymethylphosphonic acid (XVII). The same procedure, applied to the corresponding aminophenethyl alcohols, afforded: 2-(4-aminophenyl)ethoxymethylphosphonic acid (XVI) and 2-(3,5-diamino phenyl)ethoxymethylphosphonic acid (XVIII). The synthesized compounds were tested in vitro on cell cultures for the cytostatic and antiviral activity (HSV-1, HSV-2, VSV, VZV, CMV). No antiviral activity has been found for any of the compounds.