An optimized approach in the synthesis of imatinib intermediates and analogues

Abstract

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.

<p>Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib</p>

“…The synthesis of the intermediates 2, 4–6 and 8–10 , as well as of the final compounds, imatinib analogues I–IV , were based on a recently described optimized approach in the synthesis of imatinib intermediates and analogues and its spectroscopic data are consistent with the reported ones 42. The experimental procedure for the final step of the target compounds, V – VIII , and specific details are given below.…”

“…The synthesis of imatinib and all imatinib ( I-IV ), nilotinib ( V, VI ) and imatinib/nilotinib ( VII, VIII ) analogues (Figure 1), as mentioned above, were based on a recently described by us improved and efficiently optimized approach in the preparation of imatinib and/or nilotinib analogues 42. The imatinib analogues, compounds I-IV , and the imatinib/nilotinib analogues, compounds VII and VIII , containing the urea moiety, were prepared as shown in Scheme 1.…”

Mild alkaline hydrolysis of hindered esters in non-aqueous solution

“…It is worth noting also that, in some of these cases, conventional methods for hydrolysis of carboxylic esters in aqueous solution did not take place under basic conditions. [11][12][13][14][15][16][17][18][19] Moreover, the method has been applied to the hydrolysis of several sulfonates. 20 Very recently, in an attempt to hydrolyse a methyl-ester moiety on a substrate also possessing a tert-butyl ester group using our methodology, we were surprised to find that the tert-butyl group was also removed.…”

Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives

“…1) [26] conserved in its structure; the drug is efficacious in imatinib resistant cases [27]. On the basis of above and considering the literature reports discussing Abl-imatinib structural interactions [16,[26][27][28][29][30][31][32], we decided to conjugate the scaffolds based on 2-pyridone [21,33,34], benzopyran-2-one [35], benzopyran-4-one [22,36], indole acetic acid, iso-nicotinic acid, hippuric acid, piperic acid, 2-oxoquinolinacetic acid, 3-oxobenzooxazinacetic acid [37], and trimethoxyphenyl acrylic acid [38], with PPAP moiety to form the amide/cyclic amide derivatives.…”