5-(4-Methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzenamine

Beige Solid

To 400 mL of N-methyl-2-pyrrolidone, 80.0 g (261 mmol) of compound [1] and 0.43 g (5.2 mmol) of cyclohexene were added, and 43.5 g (366 mmol) of thionyl chloride was added dropwise at 20 to 40 C., followed by 60 C. The temperature was raised and the reaction was carried out for 1 hour. After confirming the reaction end point, a solution prepared by dissolving 63.0 g (261 mmol) of compound [3] in 400 mL of N-methyl-2-pyrrolidone was added dropwise to the reaction mass, and the mixture was reacted at 60 C. for 3 hours. After 400 mL of water was introduced into the reaction mass, the temperature was raised to 80 C, 83.0 g of a 20% KOH aqueous solution was added dropwise, and the temperature was kept at 80 C for 3 hours or more.Subsequently, 112.3 g of a 20% KOH aqueous solution was added dropwise over 1 h. After cooling to 60 C., 45.2 g of a 40% K 2 CO 3 aqueous solution was added dropwise, and the mixture was cooled to 40 C. over about 2 hours. The obtained crystals were dried under reduced pressure to obtain 128.6 g of compound [4] (nilotinib) (yield 93.0%). The area percentage of the peak of the target substance in the LC chromatogram was 99.96% (nuclear chlorinated product was not detected).General procedure: To a solution of chloroanhydride in dry CHCl3 was addedamine R2NH2 (one equivalent) and Et3N (1.5 equivalents). The reaction mixture was stirred atroom temperature. The reaction progress was monitored by TLC. Cold water was added to thereaction mixture. The organic layer was separated from the water. The combined organic layers weredried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by columnchromatography on silica gel.General procedure: A mixture of acid 7b (or 7c) (1.3 equivalents), 1-hydroxybenzotriazole (1.3 equivalents), andN, N?-dicyclohexylcarbodiimide or 1, 1?-carbonyldiimidazole (1.3 equivalents) was dissolved in dryDMF. Et3N (2.5 equivalents) and amine R2NH2 (one equivalent) were added. The resulting mixture was stirred at room temperature. The reaction progress was monitored by TLC. The solvent wasremoved under reduced pressure. The crude was diluted with water, and NH4OH was added to obtainpH = 10-11. The resulting solid was filtered and washed with water. The product was purified bycolumn chromatography on silica gel.General procedure: To a solution of chloroanhydride in dry CHCl3 was addedamine R2NH2 (one equivalent) and Et3N (1.5 equivalents). The reaction mixture was stirred atroom temperature. The reaction progress was monitored by TLC. Cold water was added to thereaction mixture. The organic layer was separated from the water. The combined organic layers weredried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by columnchromatography on silica gel.General procedure: To a solution of chloroanhydride in dry CHCl3 was addedamine R2NH2 (one equivalent) and Et3N (1.5 equivalents). The reaction mixture was stirred atroom temperature. The reaction progress was monitored by TLC. Cold water was added to thereaction mixture. The organic layer was separated from the water. The combined organic layers weredried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by columnchromatography on silica gel.General procedure: To a solution of chloroanhydride in dry CHCl3 was addedamine R2NH2 (one equivalent) and Et3N (1.5 equivalents). The reaction mixture was stirred atroom temperature. The reaction progress was monitored by TLC. Cold water was added to thereaction mixture. The organic layer was separated from the water. The combined organic layers weredried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by columnchromatography on silica gel.General procedure: To a solution of chloroanhydride in dry CHCl3 was addedamine R2NH2 (one equivalent) and Et3N (1.5 equivalents). The reaction mixture was stirred atroom temperature. The reaction progress was monitored by TLC. Cold water was added to thereaction mixture. The organic layer was separated from the water. The combined organic layers weredried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by columnchromatography on silica gel.General procedure: To a solution of chloroanhydride in dry CHCl3 was addedamine R2NH2 (one equivalent) and Et3N (1.5 equivalents). The reaction mixture was stirred atroom temperature. The reaction progress was monitored by TLC. Cold water was added to thereaction mixture. The organic layer was separated from the water. The combined organic layers weredried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by columnchromatography on silica gel.To a solutionof amine 3-(4-methyl-1H-imidazol-1-yl)-5-(triuoromethyl)aniline (a) (one equivalent) and Et3N(1.5 equivalents) in dry CHCl3 cooled to 0 C was added dropwise to a solution of4-(chloromethyl)benzoyl chloride (4) (one equivalent) in dry CHCl3. The reaction mixture wasstirred at room temperature. The progress was monitored by TLC. Cold water was added to thereaction mixture. The organic layer was separated, and the water layer was extracted by CHCl3 threetimes. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum.The product was purified by column chromatography on silica gel. The white solid 5 was given with 60% yield; m.p. 80-82 C; 1H-NMR (DMSO-d6, 500 MHz) : 10.74 (s, 1H), 8.32 (s, 1H), 8.26 (d, J = 1.0 Hz, 1H), 8.17 (s, 1H), 8.03 (d, J = 8.3 Hz, 2H), 7.77 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.52 (s, 1H), 4.89 (s, 2H), 2.21 (s, 3H); 13C-NMR (DMSO-d6, 125 MHz) : 166.1, 142.2, 141.7, 139.4, 138.4, 135.5, 134.4, 129.4, 128.6, 115.4, 114.7, 112.2, 45.8, 14.0; HRMS (ESI+) m/z calculated for C19H16ClF3N3O [M + H]+394.0929, found 394.0927; purity: 97.93% (by HPLC).

Intermediate in the preparation of Nilotinib.

Molecular Weight:241.21
XLogP3:2.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:241.08268182
Monoisotopic Mass:241.08268182
Topological Polar Surface Area:43.8
Heavy Atom Count:17
Complexity:269
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes