反应详情

温度

90 °C

A mixture of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (0.2 g, 0.44 mmol), 1-acetyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (0.10 g mg, 0.43 mmol) was taken in 2,2,2-trifluoroethanol (10 mL) and hydrochloric acid (1.0 mL, 4.0 mmol, 4M in 1,4-dioxane) was added. The mixture was heated at 90° C. in a sealed tube for 24 h. The reaction was cooled; excess saturated aqueous sodium bicarbonate was added, 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 (5.0 mL, 10 mmol, 2M in THF). The reaction was stirred for 16 h, diluted with water, and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, concentrated, and purified by flash silica gel column chromatography (0 to 20% methanol/dichloromethane spiked with aqueous ammonia). “Pure” fractions were isolated, concentrated, dissolved in 1,4-dioxane (7.0 mL), treated with 85% potassium hydroxide (750 mg, 11.4 mmol), water (1.0 mL), and stirred for 24 h at 80° C. The reaction was cooled; the organic layer was separated, dried over sodium sulfate, and purified by flash silica gel column chromatography. Further purification via reverse phase HPLC (5 to 90% acetonitrile/water, 0.05% trifluoroacetic acid) provided 2-[(2-{[1-acetyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.03 g, 0.06 mmol, 14% over 3 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.92 (m, 2 H), 2.16 (s, 3 H), 2.64-2.72 (m, 2 H), 2.78 (d, J=4.2 Hz, 3 H), 3.68 (t, J=6.2 Hz, 2 H), 3.87 (s, 3 H), 6.32 (bs, 1 H), 6.84 (m, 1 H), 6.94-7.03 (m, 2 H), 7.40-7.47 (m, 1 H), 7.50 (s, 1 H), 8.17-8.26 (m, 1 H), 8.46 (s, 1H), 8.52-8.59 (m, 1 H), 10.07 (s, 1 H), 11.42 (bs, 1 H); ESIMS (M+H)+=504.

1. temperatureThe reaction was cooled
2. extractionextracted with dichloromethane
3. customThe organic layer was separated
4. dry with materialdried over magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated
7. additiondiluted with tetrahydrofuran (10 mL)
8. extractionextracted with ethyl acetate
9. customThe organic layer was separated
10. dry with materialdried over sodium sulfate
11. concentrationconcentrated
12. custompurified by flash silica gel column chromatography (0 to 20% methanol/dichloromethane spiked with aqueous ammonia)
13. custom“Pure” fractions were isolated
14. concentrationconcentrated
15. dissolutiondissolved in 1,4-dioxane (7.0 mL)
16. stirringstirred for 24 h at 80° C
17. temperatureThe reaction was cooled
18. customthe organic layer was separated
19. dry with materialdried over sodium sulfate
20. custompurified by flash silica gel column chromatography
21. customFurther purification via reverse phase HPLC (5 to 90% acetonitrile/water, 0.05% trifluoroacetic acid)