This article is dedicated to Professor Dieter Seebach, in recognition for his great contribution in Organic ChemistryWe revisited the classical synthetic procedure for Imatinib synthesis providing an improved and optimized approach in the preparation of a series of new Imatinib analogues. The proposed methodology effectively overcomes certain problematic steps, saves time and labor, provides a very high yield and purity and has the potential to be used for the synthesis of many analogues. Τhe formation of the desired guanidine salt 4, one of the key steps to the Imatinib synthesis, was procedeed almost quantitatively by the reaction of the hydrochloride of the suitable aniline 3 with excess of molten cyanamide, without any solvent. Pure arylamine intermediates 6a-d were obtained quantitatively in a short reaction time after reduction of the nitro group of the intermediate pyrimidines 5a-d with hydrogen over the Adam's catalyst. In addition, the application of this optimized approach can be extended in the synthesis of Nilotinib and its analogues intermediates.

During the N-benzoylation reaction for the synthesis of N-substituted aminopyrimidines, an undesired N,N-diacylation reaction took place. The extension of this N-acylation reaction to a series of several 2-aminopyrimidines, aminopyrazines and highly deactivated anilines produced analogous results. The possible mechanism responsible for that behavior is investigated and an advantageous alternative procedure for the clean formation of the desired amides is suggested.