Diisopropylethylamine → 4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)-6-(1-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

Participants

Reaction Steps

Hunig's base (0.014 mL, 0.079 mmol) was added to a stirred solution of crude 2-(4-(3-carbamoyl-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)acetic acid (20 mg, from Step 2) and HATU (20.05 mg, 0.053 mmol). After 2.5 h at room temperature, 3,3-difluoroazetidine hydrochloride (6.83 mg, 0.053 mmol) was added. After 40 min at room temperature, the reaction was complete. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 7-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.1 mg). 1H NMR (500 MHz, chloroform-d/methanol-d4) δ ppm 8.31 (br. s., 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.63 (dd, J=8.9, 1.5 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.49 (d, J=8.9 Hz, 1H), 4.99-4.91 (m, 3H), 4.46 (t, J=11.9 Hz, 2H), 4.39 (t, J=11.9 Hz, 2H), 3.94 (br. s., 2H), 3.41 (br. s., 1H), 2.84 (br. s., 1H), 1.29 (d, J=6.9 Hz, 3H); MS (ES+) m/z: 561.1 (M+H); LC retention time: 1.24 min (analytical LCMS Method I).

Provenance & Evidence