(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

1196508-04-9

1196541-47-5

(0010) To a 1 L inert jacketed reactor equipped with a mechanical stirrer, nitrogen/vacuum manifold, thermocouple, and condenser was added (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine (1:1 toluene solvent compound) (30.0 g, 1.00 equiv) and tetrahydrofuran ( 180 mL, 6.00 mL/g). Subsequently, 4.5 M piperazine aqueous solution (42.4 g dissolved in 190 mL of water) was slowly added to the reaction mixture while maintaining the temperature at 0 °C. Next, sulfuric acid (36.1 mL, 3.00 eq.) was added and the reaction mixture was stirred at 25 °C for 2 hours. Upon completion of the reaction, 15.0 mL of saturated brine was added and the aqueous phase was separated. The organic phase was stirred for 5 minutes at 20 °C before water (22.0 mL) was added and subjected to continuous distillation at 50 °C. The ethanol feed rate was adjusted to match the distillation rate by adjusting the ethanol feed rate until a total of 260 mL of ethanol was added. Subsequently, water (340 mL) was added over a period of 1 hour at 50 °C. The resulting solid was separated by filtration and washed with 20% aqueous ethanol (2 x 60 mL). Finally, drying in a vacuum oven at 50 °C overnight gave 16.4 g (78% corrected yield) of (R)-5-bromo-4-(3-aminopiperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid. Note: The 1H NMR and 13C NMR spectra of the free base product have broader signals, so the spectra shown are after conversion of the free base to the bis-HCl salt.1H NMR (300 MHz, DMSO-d6): δ 11.98 (br, 1H), 9.78 (s, 1H), 8.44 (br, 3H), 8.25 (s, 1H), 7.45 (d, J = 2.4 Hz, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.41 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.90 (penta, J = 6.5 Hz, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 1.52 (m, 1H ), 0.83 (m, 4H).13C NMR (75 MHz, DMSO-d6): δ 172.9, 149.5, 145.9, 145.1, 121.9, 114.2, 113.1, 107.8, 53.8, 51.1, 47.5, 28.6, 24.37, 14.7, 7.55, 7.45.HRMS- ESI (m/z): [M + H]+ calculated value C16H21BrN5O, 378.0924; measured value, 378.0912.