Formylation of 2-methylpyrimidine-4,6-diol under the conditions of the Vilsmeier-Haack reaction

Quite a lot of active pharmaceutical ingredients with various pharmacological effects have been obtained based on pyrimidine hydroxy derivatives. Our attention was drawn to 2-methylpyrimidine-4,6-diol (1). Its 5-formyl derivative has potentially antihypertensive activity with a high probability according to in silico screening data. For the implementation of formylation, the Vilsmeier-Haack method was chosen as the most powerful and effective among the known methods for introducing a formyl group into heterocyclic systems. The aim of the work is to study the Vilsmeier-Haack reaction for substrate 1, to select optimal conditions for obtaining the maximum practical yield with the shortest synthesis time. In the course of the work, the influence of the conditions of the Vilsmeier-Haack reaction for 2-methylpyrimidine-4,6-diol. A comparative analysis of approaches using various solvents (o-xylene,
N,N-dimethylformamide (DMFA), benzene and dichloroethane) as the reaction medium and the optimal one was selected. The amount of Vilsmeier reagent and substrate 1 was strictly equivalent. During the formylation of substrate 1 under the conditions of the Vilsmeier-Haack reaction in the medium of o-xylene, DMFA, benzene and dichloroethane, only 4,6-dihydroxy-2-methylpyrimidine-5-carbaldehyde (2). It should be noted that there was no substitution of hydroxyl groups for chlorine atoms observed in reactions with similar substrates. The synthesis was monitored using the thin-layer chromatography method. The structure of the resulting product 2 was proved using NMR spectroscopy on ¹H and ¹³C nuclei and confirmed by mass spectrometry. Formylation in DMFA medium is characterized by the highest practical yield of product 2, shorter synthesis time, and minimal solvent costs.