The use of protecting groups in the synthesis of purine derivatives (review)

Abstract

During the synthesis of derivatives of purine from amino-, hydroxy-, thio-, or chloropurines there is often a need at position 2, 6, 7, or 9 of the purine ring to insert a protecting group that can be removed after the necessary chemical operations and retained or replaced by another pharmacophoric group during the search for biologically active substances. ALKYL (ARALKYL) PROTECTION OF POSITION 7(9)The following basic rules were established on the basis of experimental data from a large number of papers and patents relating to the nucleophilic substitution of chloropurines, reported in the monographs [1, 2]: In the series of chloro-, dichloro-, and trichloropurines the most reactive is the chlorine atom at position 6, in second place is the chlorine atom at position 8, and in third place the chlorine atom at position 2 of the purine bicycle. This rule persists in the series of 7(9)-alkyl-2,6-, -2,8-, and -6,8-dichloropurines.In the series of 7(9)-alkyl-2,6,8-trichloropurines the order of nucleophilic substitution of the chlorine atoms changes. In these compounds, unlike 2,6,8-trichloropurine, the most vulnerable center for nucleophilic attack is the chlorine atom at position 8 and then the chlorine atom at position 6 of the purine ring. The chlorine atom at position 2 was and remains the most inert in the series of 7(9)-alkyl-2,6,8-trichloropurines.In the synthesis of 8-substituted purines from 2,6,8-trichloro-7-methylpurine (1) the founder of purine chemistry E. Fischer used the methyl group as protection. Thus, 2,6-dichloro-7-methylpurin-8-one (2) was obtained by the reaction of the trichloride 1 with KOH in aqueous solution at 20°C [3].