Synthesis 6-Perfluoroalkylpyrimidine Analogues of Imatinib

Terentjeva, S.; Muceniece, D.; Lusis, V. K.

doi:10.3184/174751915x14473498225894

Cited by 2 publications

(3 citation statements)

References 6 publications

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“…When present at C3, the carboxamide and, to a lesser extent, the ester are compatible (entries 26 and 23); this order is reversed when these groups are moved to the C1' position (entries 24 and 27). These results are difficult to rationalize due to the low stability of aldehyde-and ketone-containing (Table 1, entries 13-18) and amine-based ferrocenes (entries [28][29][30][31][32][33]. Furthermore, steric hindrance can be invoked in the case of CONiPr 2 at C2 (entry 25) while coordination can be advanced for CN (entries [19][20][21].…”

Section: Oxidative Addition As Rate Determining Stepmentioning

confidence: 99%

“…Indeed, although it was in palladium-catalyzed amination, Hartwig and co-workers showed that reductive elimination with CÀ N bond formation was influencing for series of five-membered heteroaryl halides, with less electron-rich aryl moiety favoring the process. [31] To this purpose, the Mulliken charges on carbons were calculated (Table 4; B3LYP calculations with a 6-31G(d) basis set). These calculations show that the introduction of substituents at C3 or C1' have a very limited impact on the electron-rich character of the ferrocenyl group.…”

Section: Comparison With the Corresponding Benzenesmentioning

confidence: 99%

“…Indeed, similar couplings between amides and iodobenzenes bearing for example 3-CH 2 OH, 3-COMe, 3-CN, 4-CONHR and 4-CO 2 R can be carried out in good yields. [10] However, when more elaborated aryl iodides [3,[6][7]9,31] or iodinated heteroaromatics [8,32] are similarly reacted with amides, lower yields are more commonly obtained.…”

Section: Comparison With the Corresponding Benzenesmentioning

confidence: 99%

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On the N‐Arylation of Acetamide Using 2‐, 3‐ and 1’‐Substituted Iodoferrocenes**

et al. 2020

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Various 2-, 3-and 1'-substituted iodoferrocenes were reacted with acetamide in the presence of copper(I) iodide (1 equiv), N,N'-dimethylethylenediamine (1 equiv), tripotassium phosphate (2 equiv) in dioxane at 90°C for 14 h, and allowed a large range of original 1,2-, 1,3-and 1,1'-disubstituted ferrocenes to be obtained. The results were compared as a function of the substituent and its position on the ring. DFT calculations revealed higher activation barrier for the oxidative addition in the ferrocene series when compared with classical planar aromatics. Structure-property relationships were applied to rationalize the reactivity of the different iodoferrocenes.

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Section: Oxidative Addition As Rate Determining Stepmentioning

confidence: 99%

Section: Comparison With the Corresponding Benzenesmentioning

confidence: 99%

Section: Comparison With the Corresponding Benzenesmentioning

confidence: 99%

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On the N‐Arylation of Acetamide Using 2‐, 3‐ and 1’‐Substituted Iodoferrocenes**

et al. 2020

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Synthesis of Novel 3-Substituted Benzamides Related to Imatinib

Terentjeva

Muceniece

Petushkova

et al. 2016

Journal of Chemical Research

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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

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Synthesis 6-Perfluoroalkylpyrimidine Analogues of Imatinib

Abstract: 6-Perfluoroalkyl pyrimidine derivatives of well known tyrosine kinase inhibitor imatinib have been synthesised from 1-(pyridin-3-yl)-3perfluoroalkylbutane-1,3-diones by condensation with a 3-iodophenylguanidine and then by a Cu(I)-catalysed reaction with a 4-substituted benzamide.

Cited by 2 publications

References 6 publications

On the N‐Arylation of Acetamide Using 2‐, 3‐ and 1’‐Substituted Iodoferrocenes**

On the N‐Arylation of Acetamide Using 2‐, 3‐ and 1’‐Substituted Iodoferrocenes**

Synthesis of Novel 3-Substituted Benzamides Related to Imatinib

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