N,N'-Dimethylethylenediamine → ethyl 4-[5-fluoro-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-oxopiperazine-1-carboxylate

Participants

Reaction Steps

3-Bromo-5-fluoro-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (0.233 g, 0.693 mmol), 3-oxo-piperazine-1-carboxylic acid ethyl ester (0.131 g, 0.762 mmol), N,N′-dimethylethane-1,2-diamine (0.031 mL, 0.284 mmol), copper(I) iodide (0.029 g, 0.152 mmol), potassium phosphate (tribasic, n-hydrate) (0.162 g, 0.762 mmol), and 1,4-dioxane (15 mL) are added together under a nitrogen atmosphere, and heated to reflux overnight with stirring. Further copper (I) iodide (0.120 g, 0.630 mmol) and N,N′-dimethylethane-1,2-diamine (0.120 mL, 1.099 mmol) are then added and the reaction kept at 105° C. for a further 5 h. The reaction is cooled, poured onto brine (ca. 50 mL) and the product extracted with CHCl3 (ca. 3×30 mL). The combined organic extracts are diluted with MeOH, and poured on to a SCX2 ion-exchange column. This is flushed with one column volume of MeOH, and then the product collected in the subsequent one column volume flush of 7 M methanolic ammonia. The solution is then concentrated in vacuo to give a brown oil. This is purified by supercritical fluid chromatography (RT=4.7 minutes (UV); SFC Column. Benzenesulphonamide 21.2 mm×500 mm 5 μm; CO2 Gradient: 15-30% MeOH w/0.2% DMEA in 5.5 mins and then ramped up to 50% MeOH and held for 3.5 mins; Column Temp: 40° C.; Flow Rate: 50.0 ml/min) to give an orange solid. This is then further purified by HPLC chromatography (RT=4.67 minutes (UV); LC Column. Waters Xbridge C18 100 mm×30 mm 5 μm; H2O w/0.2% NH4HCO3 Gradient: 9-100% ACN w/0.2% NH4HCO3 in 6.0 min then held at 100% for 3.0 min; Column Temp: 50° C.; Flow Rate: 3.0 ml/min) to give the title compound as a white solid (0.0621 g, 0.145 mmol). MS (m/z): 428 (M+1). 1H-NMR (300.13 MHz, CDCl3): δ 1.32 (t, 3H), 3.72 (s, 3H), 3.73-3.80 (br, 2H), 3.84-3.89 (br, 2H), 4.22 (q, 2H), 4.34 (br, 2H), 5.66 (s, 2H), 7.03 (s, 1H), 7.21 (t, 1H), 7.49 (d, 1H), 7.51-7.55 (m, 1H), 7.70 (td, 1H), 8.60 (d, 1H).

Provenance & Evidence