[Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[CH:12][N:11]=1.[CH2:16]([CH2:18][NH2:19])[OH:17].C(=O)(O)[O-].[Na+]>C1COCC1.CC(C)=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:19][CH2:18][CH2:16][OH:17])[CH:5]=[C:4]([NH2:9])[C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[CH:12][N:11]=1To a solution of 2,4-dichloro-6-aminophenyl-1,3,5-triazine (1.6 g, 6.6 mmol) in THF (70 mL) at room temperature was added a solution of ethanolamine (439 mg, 7.3 mmol) in acetone (24 mL) and water (24 mL), followed by 5% aqueous sodium bicarbonate (15 mL). The reaction was stirred for 20 h at room temperature. The mixture was then diluted with water (25 mL) and ethyl acetate (25 mL). The aqueous layer was extracted with ethyl acetate (2×25 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude residue was purified on a Biotage™ 40S column (silica, hexane/AcOEt 9:1 to 0:1) to yield 2-chloro-4-(2-hydroxyethylamino)-6-aminophenyl-1,3,5-triazine as a white solid (1.6 g, 91% yield). This compound (710 mg, 2.7 mmol) was dissolved in THF (26 mL) and 2-(4-aminophenyl)ethylamine (1.1 mL, 8.0 mmol) was added followed by triethylamine (1.1 mL, 8.0 mmol). The reaction was stirred for 20 h at 60° C. and then diluted with methanol (20 mL). Solvent was removed under reduced pressure and the crude residue was purified on a Biotage™ 40S column (silica, AcOEt/MeOH 1:0 to 9:1) to yield 2-[2-(4-aminophenyl)ethylamino]-4-(2-hydroxyethylamino)-6-phenylamino-1,3,5-triazine as an off-white solid (916 mg, 91% yield). To a solution of 2,4-dichloro-6-aminophenyl-1,3,5-triazine (356 mg, 1.5 mmol) in THF (30 mL)/acetone (11 mL)/water (11 mL) was added a solution of 1,3,5-triazine derivative above (540 mg, 1.5 mmol) in THF (14 mL) followed by 5% sodium bicarbonate, solution (10 mL). The reaction was stirred for 20 h at room temperature and the solution diluted with water (30 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL). The organic layers were washed with brine (40 mL), dried over anhydrous sodium sulphate and filtered. This gave 2-{4-[2-(4-{4-chloro-6-phenylamino-[1,3,5]triazin-2-ylamino}phenyl)-ethylamino]-6-phenylamino-[1,3,5]triazin-2-ylamino}-ethanol as an off-white solid (860 mg, quantitative yield). The product was used for the next step without further purification. To a solution of this compound (41 mg, 0.1 mmol) in THF (1 mL) was added 2-(4-aminophenyl)ethylamine (28 μL, 0.2 mmol) followed by triethylamine (30 μL, 0.2 mmol). After 20 h of reaction at 50° C., the solution was diluted with methanol (5 mL) and concentrated under reduced pressure. The crude residue was purified on a Biotage™ 12 M column (silica, AcOEt/MeOH 1:0 to 9:1) to yield compound 17 as a white solid. Yield of product: 30 mg (79%), 1H NMR (400 MHz, CD3OD) δ7.63-7.39 (m, 6H), 7.14 (m, 4H), 7.04 (d, 2H, J=8.6; H), 6.86 (m, 4H), 6.56 (d, 2H, J=7.8 Hz), 3.59 (m, 2H), 3.43 (m, 6H), 2.75 (m, 2H), 2.66 (t, 2H, J=7.5 Hz); LRMS (ESI): m/z 670.2 (MH+); HPLC (method 2): 4.3 min.
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