Specific enzyme inhibitors in vitamin biosynthesis. Part I. The synthesis of 8-substituted pyrido[2,3-d]pyrimidines

Abstract

Two methods for the synthesis of 8-substituted pyrido[2,3-d]pyrimidines are described. These compounds are close structural analogues of the pteridine precursor involved in the biosynthesis of riboflavin, and were required for studies of the inhibition of riboflavin synthetase.

The first method is an adaptation of the Doebner–Miller synthesis of quinolines and is a new route to the pyrido[2,3-d]pyrimidine ring system. It involves condensation of a 6-(substituted amino)uracil with an αβ-unsaturated carbonyl derivative, and leads initially to an unusual tricyclic intermediate. Detailed spectroscopic studies on this intermediate helped to elucidate the structure of the final products.

The second method involved condensation of 6-(substituted amino)uracils with β-dicarbonyl derivatives. The resulting pyrido[2,3-d]pyrimidines were different from those expected on the basis of earlier work.

¹ H N.m.r. studies of the 8-substituted pyrido[2,3-d]pyrimidines showed that deuterium exchange of protons on C-methyl groups at positions 5 and 7 took place readily in alkaline solution, whereas protons on a 6-methyl group did not exchange. This phenomenon is similar to that observed with the pteridine precursor involved in riboflavin biosynthesis, and an explanation involving a highly delocalised anionic species is offered.