Diisopropylethylamine → 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione

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Reaction Steps

To a 250 mL flask was added 5-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (2.250 g, 10.7 mmol) and 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.75 g, 9.19 mmol). The mixture was diluted with DMF (100 mL) and Hunig's Base (16.6 mL, 95 mmol) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4 g, 12.46 mmol) was added to the mixture. The mixture was stirred at rt for 70 h, quenched with water (50 mL) and the solvent removed under reduced pressure. The residue was diluted with water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the residue purified by BIOTAGE® flash chromatography using a 0-5% MeOH in dichloromethane gradient. The residue still had impurities by 1H NMR so it was dissolved in dichloromethane (150 mL) and washed with sat. NaHCO3 (100 mL) then with sat. ammonium chloride (150 mL). The organic solution was dried with Na2SO4, the drying agent was removed by filtration, and the solution was concentrated under reduced pressure to give 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (3.40 g, 6.92 mmol, 75% yield) as a blue solid. The product still had some impurities by 1H NMR, but was used in the next step with no additional purification. LC/MS: m/z 489.14 (M+H)+, 1.169 min (method 1). 1H NMR (500 MHz, chloroform-d) δ ppm 10.89 (br. s., 1H) 8.62-8.80 (m, 1H) 7.64-7.95 (m, 3H) 6.98-7.49 (m, 5H) 4.66-4.99 (m, 2H) 3.60-3.87 (m, 5H) 2.87-3.12 (m, 2H).

Provenance & Evidence