反应详情

A solution of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (500 mg, 1.043 mmol) and 1-[(dimethylamino)acetyl]-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (333 mg, 1.200 mmol) in THF (8 ml) was warmed to 75° C. in a sealed pressure vial for 16 hours. The solution was concentrated under reduced pressure, suspended in dichloromethane, and washed with saturated sodium bicarbonate. The organic layer was taken to a residue under reduced pressure and triturated with diethyl ether to afford 5-{[1-(N, N-dimethylglycyl)-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.472 g, 0.690 mmol, 66.2%) as a pale greenish yellow solid. A solution of 5-{[1-(N,N-dimethylglycyl)-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8′-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.472 g, 0.690 mmol) and 2.0M methyl amine in THF (2.76 ml, 5.52 mmol) in THF (40 ml) was stirred for 3 hours at room temperature. The reaction was poured into saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, redissolved in 1,4-dioxane (8 ml) and added to a microwave-safe vial with 2.0N NaOH (aq) (8 ml). The contents were warmed to 120° C. under microwave irradiation with rapid stirring for 12 minutes, cooled to room temperature, and poured into THF/ethyl acetate/saturated/sodium bicarbonate (aq). The organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography to afford 2-[(2-{[1-(N,N-dimethylglycyl)-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.202 g, 0.360 mmol, 52.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.26 (s, 1H), 10.14 (s, 1H), 8.56 (s, 1H), 8.54 (d, J=4.61 Hz, 1H), 8.34 (d, J=8.43 Hz, 1H), 7.58 (s, 1H), 7.25-7.35 (m, 1H), 6.93-7.00 (m, 2H), 6.85-6.93 (m, 1H), 6.21-6.32 (m, 1H), 3.93 (s, 2H), 3.79 (s, 3H), 3.17 (s, 2H), 2.79 (d, J=4.41 Hz, 3H), 2.24 (s, 6H), 1.32 (s, 6H). ESIMS (M+H)+=561.

1. concentrationThe solution was concentrated under reduced pressure
2. washwashed with saturated sodium bicarbonate
3. customtriturated with diethyl ether