Collect. Czech. Chem. Commun. 2004, 69, 1889-1913

Synthesis of N9- and N7-[2-Hydroxy-3-(phosphonomethoxy)propyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds

Marcela Krečmerová*, Milena Masojídková and Antonín Holý

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


Base-catalyzed reactions of diethyl [(oxiranylmethoxy)methyl]phosphonate (2) with purine bases (adenine, 2,6-diaminopurine, 6-chloropurine and 2-amino-6-chloropurine) gave corresponding 9- or 7-[2-hydroxy-3-(phosphonomethoxy)propyl] purines. The adenine and 2,6-diaminopurine derivatives cyclize to cyclic phosphonates 4 and 6. The 9-[2-hydroxy-3-(phosphonomethoxy)propyl] derivatives of N6-substituted adenine and 2,6-diaminopurine (15-27) were prepared by the treatment of diethyl {[3-(6-chloropurin-9-yl)-2-hydroxypropoxy]methyl}phosphonate (11) or diethyl {[3-(2-amino-6-chloropurin-9-yl)-2-hydroxypropoxy]methyl}phosphonate (13) with primary or secondary amines. The reaction of 6-chloro- or 2-amino-6-chloropurine derivatives (11, 13) with thiourea gave the corresponding diethyl purine-6-thiol or 2-aminopurine-6-thiol phosphonates 47, 48. The guanine derivative 49 was prepared by the treatment of compound 13 with 80% acetic acid. All diethyl phosphonates were transformed to free phosphonic acids (31-43, 50-52) by the action of bromotrimethylsilane and subsequent hydrolysis.

Keywords: Acyclic nucleotide analogues; Phosphonates; Purines; Oxirane ring opening; Epoxides; Nucleotides; Nucleosides; Antivirals; HPMPA.

References: 21 live references.