反应详情
EQUATION
反应方程式
REACTANTS
反应物
PRODUCTS
生成物
AUXILIARIES
试剂、催化剂与溶剂
CONDITIONS
反应条件
- 温度
- 80 °C
PROCEDURE
实验过程
A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (0.550 g, 1.147 mmol) and 5-chloro-1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (0.291 g, 1.147 mmol) in tetrahydrofuran (20 ml) was maintained at 80° C. in a pressure vessel for 16 hours. The vessel was cooled, THF removed under reduced pressure, and the solids were partitioned between methylene chloride/trifluoroethanol/saturated sodium bicarbonate. The organic layer was taken to a residue under reduced pressure and triturated with diethyl ether to afford 5-{[5-chloro-1-(N,N-dimethylglycyl)-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 (0.550 g, 0.833 mmol, 72.6%) as a reasonably pure (ca 70-80%) green solid. A solution of 5-{[5-chloro-1-(N,N-dimethylglycyl)-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 (0.550 g, 0.833 mmol) and 2.0M methyl amine/THF (2.500 ml, 5.00 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature for 5 hours. The reaction was stripped directly onto celite and purified by column chromatography to afford the intermediate tosylate as a yellow foam. This intermediate was dissolved in 1,4-dioxane (8 ml) and added to a microwave vial with 2.0N NaOH (aq) (8 ml). Microwave heating at 120° C. for 12 minutes was followed by cooling, dilution with ethyl acetate/saturated sodium bicarbonate/THF and the resulting organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography to afford 2-[(2-{[5-chloro-1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.068 g) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 10.19 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.32 (d, J=8.63 Hz, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 7.20-7.30 (m, 1H), 6.92-6.97 (m, J=3.01 Hz, 1H), 6.83-6.92 (m, 1H), 6.26 (dd, J=3.41, 1.81 Hz, 1H), 4.21 (t, J=8.43 Hz, 2H), 3.20 (s, 2H), 3.09-3.17 (m, 2H), 2.80 (d, J=4.61 Hz, 3H), 2.24 (s, 6H). ESIMS (M+H)+=537.
WORKUP
后处理
- temperatureThe vessel was cooled
- customTHF removed under reduced pressure
- customthe solids were partitioned between methylene chloride/trifluoroethanol/saturated sodium bicarbonate
- customtriturated with diethyl ether