4-(4-CHLORO-6-[(FURAN-2-YLMETHYL)-AMINO]-[1,3,5]TRIAZIN-2-YLAMINO)-PHENOL synthesis

Yield:311788-82-6 43%

Reaction Conditions:

Stage #1: 1,3,5-trichloro-2,4,6-triazine;furan-2-ylmethanaminewith N-ethyl-N,N-diisopropylamine in tetrahydrofuran at -20 - 0;
Stage #2: 4-amino-phenolwith N-ethyl-N,N-diisopropylamine in tetrahydrofuran at 0 - 20;

Steps:

2.45

45. 2-(4-Hydroxy-phenylamino)-4-Chloro-6-[(furan-2-ylmethyl)-amino]-[1,3,5]triazine; [0360] To a cooled to -20°^c solution of cyanuric chloride (18.44 g, 100 mmol) in anhydrous THF (200 mL) a solution of N,N-diisopropylethylamine (13.57 g, 105 mmol) and furfurylamine (9.71 g, 100 mmol) in anhydrous THF (150 mL) was added dropwise at -20°^c for a period of 30 minutes. The resulting mixture was stirred at -20°^c for 1 hour (TLC control). Then the reaction mixture was allowed to warm up to 0°^c. A solution of N₁N- diisopropylethylamine (13.57 g, 105 mmol) and p-aminophenol (10.91 g, 100 mmol) in anhydrous THF (200 mL) was added dropwise at 0°^c to the reaction mixture. The resulting mixture was stirred at 0°^c for 2 hours then at room temperature for 10 hours. The solvent was removed at reduced pressure. The crude product was purified by column chromatography on silica gel (methanol/ethyl acetate/hexane) giving 1-45 (13.66 g, 43%). ¹H-NMR (400MHz, DMSO-D₆) δ_H: 4.46 (2H, d, J=7.5 Hz); 6.24 (1 H, d, J= 7.5 Hz, broad), 6.38 (1 H, broad), 6.70 (2H, d, J= 8.6 Hz), 7.40 (2H, broad), 7.54 (1 H, d, J=1.8 Hz), 8.25- 8.40 (1 H, broad, Z/E forms), 9.20 (1H, broad), 9.50-9.70 (1 H, broad, Z/E forms). LCMS t_R (min) 1.56. MS (APCI), m/z 317.52, 319.52 [M+H]⁺. M_p 188-190°C.

References:

WO2009/91388,2009,A2 Location in patent:Page/Page column 105