P-Anisidine → N5-(4-methoxyphenyl)-N2-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridine-2,5-diamine

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A mixture of 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (0.115 g, 0.254 mmol) and 4-anisidine (0.117 mL, 1.018 mmol) (Aldrich, St. Louis, Mo.) in THF (10 mL) was treated with sodium tert-butoxide (0.073 g, 0.763 mmol) (Aldrich, St. Louis, Mo.) and 2-di-t-butylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (0.025 g) (Strem Chemicals, Inc., Newburyport, Mass.). The mixture was deoxygenated and Pd2(dba)3 (0.023 g, 0.025 mmol) (Strem Chemicals, Inc., Newburyport, Mass.) was added under N2. The flask was fitted with a reflux condenser, then placed into a pre-heated bath at 90° C. and stirred overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (10 mL) and extracted with 4:1 CH2Cl2/MeOH (5×25 mL) and from brine. The combined organic extracts were washed with saturated aqueous NaHCO3 (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as tan oil. This was adsorbed onto a plug of silica gel and purified by chromatography through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (80 g), eluting with a gradient of 1% to 5% MeOH in CH2Cl2 over 30 minutes to give N5-(4-methoxyphenyl)-N2-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridine-2,5-diamine as a tan oil. This was diluted with methanol (3 mL) and TFA (1.5 mL) and placed into a pre-heated (60° C.) bath. The mixture was allowed to stir under inert atmosphere for 2 h. The reaction mixture was allowed to cool to room temperature, concentrated in-vacuo, then diluted with DCM. The mixture was made basic with 10N aqueous NaOH, diluted with water (15 mL) and extracted with CH2Cl2 (3×15 mL). The organic extract was washed with water (1×10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a tan oil. This was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 1% to 8% MeOH in CH2Cl2 over 25 minutes, to give N5-(4-methoxyphenyl)-N2-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridine-2,5-diamine (0.009 g, 0.020 mmol, 7.78% yield) as tan solid. MS (ESI pos. ion) m/z 455 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 9.62 (s, 1H); 8.59 (s, 1H); 8.51 (s, 1H); 8.14 (m, 2H); 7.00 (d, J=8.80 Hz, 2H); 6.84 (d, J=8.80 Hz, 3H); 3.84 (s, 3H); 3.70 (s, 3H); 2.86 (s, 3H).

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