Synthesis of 6-t Rifluoromethyl Derivatives of 2-Arylamino-4-(Pyridin-3-yl) Pyrimidines

Abstract

A number of 2-arylamino-4-(pyrid-3-yl)phenylaminopyrimidines having the common structural fragment depicted in formula 1 (Fig. 1) are tyrosine kinase (TK) inhibitors, whose mode of action is to interfere with a protein having a critical role in chronic myeloid leukaemia (CML).Oncoproteins can be inhibited by various small molecules. One such inhibitor is imatinib mesylate (trade name Gleevec) 1a which occupies the tyrosine kinase domain and inhibits oncoprotein influence in the cell cycle. Nilotinib (trade name Tasigna) 1b is a novel TK inhibitor which has been developed to address the unmet medical need associated with imatinib intolerance and resistance in chronic and advanced phases of CLM. 1 The importance of the interaction between the CF 3 group of nilotinib and the target protein has been noted by Manley et al. 2 We now describe the synthesis of 6-trifluoromethyl derivative of nilotinib and some novel 6-trifluoromethylsubstituted 2-arylamino-4-(pyridin-3-yl)pyrimidines to provide compounds for testing the effect of lypophilic substituents on the activity and selectivity of TK inhibition. Results and discussionThe first step of the target compound synthesis involved the formation of core compounds 6-trifluoromethyl-2-arylamino-4-(pyridin-2-yl)pyrimidine 3a,b via reaction between 4,4,4-trifluoro-1-(pyridin-3-yl)butane-1,3-dione and the appropriate guanidine derivatives 2a,b. The diketone was fused with guanidine 2a (or 2b) hydrochloride by heating at 175°C or refluxed with guanidine 2a (or 2b) carbonate in toluene to give the corresponding pyrimidines 3a and 3b in yields of 58 and 77%, respectively. The various conversions of 3a and 3b to trifluoromethyl derivatives are shown in Scheme 2.The 2-phenylaminopyrimidines 3a,b were transformed into the target trifluoromethyl derivatives by known methods. In one approach (2-methyl-5-nitrophenyl)-4-[(pyridin-3-yl)-6-trifluoromethylpyrimidin-2-yl]amine (3a) was reduced with hydrazine hydrate and Ra-Ni to benzene-1,3-diamine derivative 4, acylation of which with 4-chlorocarbonyl benzoic acid methyl ester afforded amide 5 in high yield (98%). It should be noted that routes to various TK inhibitors include amino derivatives similar to N-pyrimidin-2-yl benzene diamine 4 as versatile intermediates of target product preparation. 3,4 To accomplish our main target, the core compound, methyl 3-(6-trifluoromethylpyrimidin-2-yl)aminobenzoate 3b was reacted with 1-(3-amino-5-trifluoromethylphenyl)-4-methyl-1H-imidazole in the presence of potassium t-butoxide to give the 6-trifluoromethyl derivative of nilotinib 7 in 67% yield (Scheme 1). All the compounds were characterised by their 1 H and 13 C NMR spectra and their elemental analysis. ExperimentalNMR spectra were obtained on a Varian 400-MR spectrometer ( 1 H NMR at 400 Hz, 13 C NMR at 100 Hz) in DMSO-d 6 except guanidine 2b carbonate. The residual solvent protons served as internal standard (2.50 ppm for 1 H nuclei and 39.5 ppm for 13 C nuclei). Chemical shifts (δ) are given in ppm and coupling constants (J) in Hz. Elemental ...