Synthesis of Novel 3-Substituted Benzamides Related to Imatinib

Abstract

N-Arylamides are prevalent in numerous compounds that are of pharmaceutical interest. Imatinib -4-(4-methylpiperazin-1-ylmethyl) -N- {4-methyl-3-[4-(pyridin-3-yl)pyrimidin-2ylamino]phenyl} benzamide (3, R = R 1 = H) mesylate -a selective tyrosine kinase inhibitor belongs to this class of compounds. The imatinib success story has stimulated the discovery of many novel inhibitors of protein kinases and further studies of imatinib derivatives promise to enhance understanding of how changes in drug structure affect biological activity. 1,2 A series of 3-substituted benzamide derivatives structurally related to imatinib was prepared and found 3 to be much more potent than the parent compound. In continuation of our research 4,5 on the synthesis of perfluoroalkyl imatinib analogous, 12 new derivatives have been prepared for biological testing by coupling three (5-iodo-2-methylphenyl)-[4-(pyridin-3-yl)-6-perfluoroalkylpyrimidin-2-yl]amines 1a-c obtained previously 5 with four 3-substituted-4-(4-methylpiperazin-1ylmethyl)benzamides 2a-d. Results and discussionThe synthetic route designed for obtaining the target compounds 3a-l is shown in Scheme 1 and employs the same Cu(I)catalysed coupling method described by us 5 for synthesising the parent analogues 3 (R = CF 3 , C 2 F 5 , C 3 F 7 , R 1 = H). The starting amides 2a-d were prepared from commercially available disubstituted benzoic acids by standard methods as shown in Scheme 2. Esterification 6 of the carboxylic acids gave methyl or ethyl esters, a-bromination 7 of which with N-bromosuccinimide and coupling 3,8 of the products with 1-methylpiperazine afforded the corresponding 3-substituted 4-(4-methylpiperazin-1-yl)benzoates which were further converted into benzamides 2a-d. These compounds were coupled with iodo compounds 1a-c in the presence of Cu(I), K 3 PO 4 and DMEDA in solvent t-BuOH under an argon atmosphere to give the 3-substituted 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-6-polyf luoromethyl-pyrimidin-2-yl-amino) phenyl] benzamides 3a-l as imatinib (3, R = R 1 = H) analogues in moderate to good yields.In some cases (synthesis of 3a, 3i), the iodide was consumed completely after 18-24 h and good yields were obtained, but for others mainly starting material (revealed by LC/MS) was present even after 48 h. For example, the coupling of iodide 1c with benzamides 2b and 2d gave low yields, which could not be improved even by a prolonged reaction time, and unconsumed iodide was recovered in 43% yield. Even when the amount of Cu(I) iodide was increased up to 100 mol%, the coupling reaction could not be effected efficiently. During the coupling of iodides 1 with bromo benzamide 2b, minor amounts of iodo derivatives 4 originated from halogen exchange could be detected. This is in agreement with the disclosure 9 of a so called aromatic Finkelstein reaction, i.e. copper-catalysed halogen exchange in aryl halides. In the case of coupling iodide 1a with amide 2b, we