反应详情

温度

120 °C

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 (0.600 g, 1.252 mmol) and 1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (0.274 g, 1.252 mmol) was maintained at 70° C. in tetrahydrofuran (20 ml) in a pressure tube for 16 hours. The reaction was cooled, opened, concentrated under reduced pressure, and redissolved in methylene chloride/2,2,2-trifluoroethanol (ca 15 mL). Saturated sodium bicarbonate was added and all solids dissolve. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and triturated with diethyl ether to afford 5-{[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 (0.696 g, 1.112 mmol, 89%) as a yellow solid. A suspension of 5-{[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 (0.696 g, 1.112 mmol) in tetrahydrofuran (20 ml) was treated with 2.0M methyl amine/THF (3.34 ml, 6.67 mmol) and over 24 hours all solids dissolve. The solution was poured into saturated sodium bicarbonate/EtOAc and the organic layer was dried over sodium sulfate, filtered, and taken to a residue under reduced pressure. The residue was dissolved in 1,4-dioxane (8 ml)/2.0N NaOH (aq) (8 ml) and maintained at 120° C. under microwave heating for 12 minutes. The solution was cooled, poured into ethyl acetate/THF/saturated sodium chloride (aq) and 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)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.230 g, 0.458 mmol, 41.1%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (s, 1H), 10.20 (s, 1H), 8.89 (s, 1H), 8.54 (d, J=7.62 Hz, 1H), 8.21 (s, 1H), 7.83 (d, J=7.22 Hz, 1H), 7.34-7.48 (m, 1H), 7.10 (d, J=8.23 Hz, 1H), 6.85-7.01 (m, 3H), 6.29 (dd, J=3.41, 1.81 Hz, 1H), 4.15 (t, J=8.23 Hz, 2H), 3.21 (s, 2H), 2.99-3.12 (m, 2H), 2.79 (d, J=4.61 Hz, 3H), 2.27 (s, 6H). ESIMS (M+H)+=503.

1. dissolutiondissolve
2. dry with materialthe organic layer was dried over sodium sulfate
3. filtrationfiltered
4. dissolutionThe residue was dissolved in 1,4-dioxane (8 ml)/2.0N NaOH (aq) (8 ml)
5. temperatureheating for 12 minutes
6. temperatureThe solution was cooled
7. additionpoured into ethyl acetate/THF/saturated sodium chloride (aq)
8. dry with materialthe organic layer was dried over sodium sulfate
9. filtrationfiltered
10. custompurified by column chromatography