Reaction Steps
A mixture of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (0.27 g, 0.54 mmol) and 1-[(dimethylamino)acetyl]-4,4-dimethyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (0.18 g, 0.60 mmol) was taken in 2,2,2-trifluoroethanol (20 mL) and heated at 90° C. for 3 h. The reaction was cooled, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, diluted with tetrahydrofuran (10 mL) and treated with excess methyl amine (10 mL, 20 mmol, 2M in THF). The reaction was stirred for 16 h at 50° C. in a sealed vial. The reaction was cooled and partitioned between water and ethyl acetate. Brine was added to assist in the separation of layers. The organic layer was separated, dried over sodium sulfate, and concentrated. The crude material was dissolved in tetrahydrofuran (10 mL), diluted with methanol (10 mL) and treated with sodium methoxide (250 mg, 4.63 mmol) and stirred at 70° C. for 3 h. The reaction was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and purified by flash silica gel column chromatography (dichloromethane to 8:1:1 mixture of dichloromethane:methano1:2M ammonia in methanol) to provide 2-[(2-{[1-(N,N-dimethylglycyl)-4,4-dimethyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.128 g, 0.223 mmol, 36% over 3 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6 H), 1.67-1.77 (m, 2 H), 2.11 (bs, 6 H), 2.78 (d, J=4.4 Hz, 3 H), 3.27 (s, 2 H), 3.75 (t, J=6.0 Hz, 2 H), 3.88 (s, 3 H), 6.29-6.34 (m, 1 H), 6.92-7.02 (s, 3 H), 7.37-7.45 (m, 1 H), 7.51 (s, 1 H), 8.18-8.27 (m, 1 H), 8.38 (s, 1 H), 8.52-8.58 (m, 1 H), 10.10 (s, 1 H), 11.39 (bs, 1 H); ESIMS (M+H)+=575.
