ethyl 3-oxopiperazine-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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). heated to reflux overnight The reaction is cooled poured onto brine (ca. 50 mL) the product extracted with CHCl3 (ca. 3×30 mL) The combined organic extracts are diluted with MeOH poured on to a SCX2 ion-exchange column This is flushed with one column volume of MeOH 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) in 5.5 mins held for 3.5 mins 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) in 6.0 min then held at 100% for 3.0 min 50° C.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromo-1-cyclopropyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (0.263 g, 765 μmol), ethyl 3-oxopiperazine-1-carboxylate (0.158 g, 0.918 mmol), N,N′-dimethylethane-1,2-diamine (33.8 μL, 0.313 mmol), copper(I) iodide (32 mg, 168 μmol), potassium phosphate (tribasic, n-hydrate) (0.179 g, 841 μmol) in DMF (10 mL) is heated at 120° C. for 15 h. The mixture is cooled to room temperature and further copper(I) iodide (0.145 g, 765 μmol), potassium phosphate (tribasic, n-hydrate) (0.536 g, 2.52 mmol) and N,N′-dimethylethane-1,2-diamine (165 μL, 1.53 mmol) are added, followed by ethyl 3-oxopiperazine-1-carboxylate (0.132 g, 0.765 mmol). After further heating for 24 h under nitrogen at 100° C., the mixture is concentrated in vacuo, diluted with MeOH and poured onto a SCX-2 ion-exchange column. This is washed with 3 column volumes of MeOH and then the product collected in the subsequent one column volume flush of 7 M methanolic ammonia. The solution is concentrated in vacuo and purified by column chromatography on silica, eluting with 0 to 100% EtOAc in isohexane, to give the title compound as a yellow oil (40 mg, 0.09 mmol). MS (m/z): 436 (M+1). 1H-NMR (400 MHz, CDCl3): 0.89-0.99 (m, 4H), 1.31 (t, 3H), 3.31-3.37 (m, 1H), 3.76-3.78 (m, 2H), 3.82-3.88 (m, 2H), 4.22 (q, 2H), 4.33 (s, 2H), 5.60 (s, 2H), 6.72 (d, 1H), 7.00 (s, 1H), 7.18-7.22 (m, 1H), 7.48-7.52 (m, 1H), 7.64-7.69 (m, 2H), 8.59-8.61 (m, 1H). The mixture is cooled to room temperature After further heating for 24 h under nitrogen at 100° C. the mixture is concentrated in vacuo diluted with MeOH poured onto a SCX-2 ion-exchange column This is washed with 3 column volumes of MeOH the product collected in the subsequent one column volume flush of 7 M methanolic ammonia The solution is concentrated in vacuo purified by column chromatography on silica eluting with 0 to 100% EtOAc in isohexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-oxo-piperazine-1-carboxylate (161.4 g, 937.2 mmol), copper(I) iodide (27.65 g, 145.20 mmol) and potassium phosphate (tribasic, n-hydrate) (205.1 g, 937.2 mmol) is charged into a glass reactor at room temperature under nitrogen. A solution of 3-bromo-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (210 g, 660.0 mmol) in 1,4-dioxane (2.73 L) is added, followed by N,N′-dimethylethane-1,2-diamine (24.34 g; 270.6 mmol). The reaction mixture is heated to 100° C. and stirred for 20 h. Further copper(I) iodide (10.06 g, 52.80 mmol) and N,N′-dimethylethane-1,2-diamine (10.95 g, 105.6 mmol) is added and the reaction stirred for a further 23 h. The reaction mixture is combined with a smaller batch made in a similar manner starting with 23.68 g of 3-bromo-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine. The mixture is cooled to room temperature, then poured into water (4.2 L) and extracted with EtOAc (3×1.7 L). The organic extracts are combined and washed with 3% w/w aqueous ammonia (3×400 mL), then water (2×2 L), then brine (600 mL), and dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica, eluting with 50 to 100% EtOAc in isohexane. The appropriate fractions are combined, evaporated and recrystallized from ethanol (525 mL). The solid is dried to give the title compound (125.6 g, 0.3 mol). MS (m/z): 410.1 (M+1). 1H-NMR (400 MHz, CDCl3): δ 1.31 (t, 3H), 3.72 (s, 3H), 3.80-3.78 (t, 2H), 3.86 (t, 2H), 4.22 (q, 2H), 4.34 (s, 2H), 5.59 (s, 2H), 6.71 (d, 1H), 7.01 (s, 1H), 7.20 (dd, 1H), 7.49 (d, 1H), 7.70-7.66 (m, 2H), 8.60 (d, 1H). DSC (onset) mp=143.42° C. the reaction stirred for a further 23 h The mixture is cooled to room temperature extracted with EtOAc (3×1.7 L) washed with 3% w/w aqueous ammonia (3×400 mL) water (2×2 L), then brine (600 mL), and dried over sodium sulphate filtered concentrated in vacuo The residue is purified by column chromatography on silica eluting with 50 to 100% EtOAc in isohexane evaporated recrystallized from ethanol (525 mL) The solid is dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-piperazinone (5.0 g, 50.0 mmol) and triethylamine (11.09 g, 110.0 mmol) in DCM (15 mL) is added ethyl chloroformate (5.9 g, 55.0 mmol) at room temperature and the reaction mixture is stirred for 2 h. The reaction is quenched with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers are dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue is triturated with Et2O to give the title compound (5.0 g, 29.05 mmol) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 1.19 (t, 3H), 3.16-3.19 (m, 2H), 3.48-3.51 (m, 2H), 3.85 (s, 2H), 4.05 (q, 2H), 8.06 (s, 1H). The reaction is quenched with water (100 mL) extracted with DCM (3×100 mL) The combined organic layers are dried over anhydrous sodium sulphate filtered concentrated in vacuo The residue is triturated with Et2O