反应详情

A mixture of 1-[(diethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (200 mg, 0.72 mmol) and 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (330 mg, 0.71 mmol) and a 4 N HCl solution in dioxane (0.7 mL, 2.87 mmol) in 2,2,2-trifluoroethanol (10 mL) was heated for 8 h in a sealed vessel at 80° C. After allowing to cool to rt half of the reaction mixture was diluted with THF (80 mL) and a 27% aqueous NH4OH solution (80 mL). The reaction mixture was stirred for 3 h and concentrated. The residue was taken up into CH2Cl2 (200 mL), concentrated onto Celite and purified by silica gel chromatography using 20% 0.5 M NH3 in dioxane/THF. The product was dissolved in THF (10 mL) and THF (20 mL) and treated with a solution of sodium methoxide (0.5M in MeOH, 4 mL, 2 mmol). The reaction mixture was stirred for 2 days, concentrated onto Celite, and purified by silica gel chromatography using 4% MeOH (containing 0.2% NH3)/CH2Cl2 then triturated using Et2O (15 mL) to obtain 2-[(2-{[1-(N,N-diethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a yellow solid (41 mg, 20% for 3 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (t, J=6.68 Hz, 6H), 2.58 (br s, 4H), 3.12 (t, J=8.15 Hz, 2H), 3.77 (s, 3H), 4.24 (t, J=8.15 Hz, 2H), 6.22 (s, 1H), 6.86 (t, J=9.43 Hz, 1H), 6.96 (s, 2H), 7.31 (q, J=7.94 Hz, 1H), 7.61 (s, 1H), 8.02 (s, 1H), 8.11 (s, 1H), 8.53 (d, J=8.24 Hz, 1H), 8.60 (s, 1H), 10.56 (s, 1H), 11.29 (s, 1H) a CH2 signal with 2 protons is missing, may overlap with water peak in sample; ESIMS (M+H)+=547.38.

1. concentrationconcentrated
2. concentrationconcentrated onto Celite
3. custompurified by silica gel chromatography
4. dissolutionThe product was dissolved in THF (10 mL)
5. stirringThe reaction mixture was stirred for 2 days
6. concentrationconcentrated onto Celite
7. custompurified by silica gel chromatography
8. customthen triturated