Diisopropylethylamine → (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

Participants

Reaction Steps

4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(3-methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (14 mg, 0.040 mmol), 1-cyanocyclopropanecarboxylic acid (6.58 mg, 0.059 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (22.53 mg, 0.059 mmol) were weighed into a vial. DMF (0.25 mL) and N,N-diisopropylethylamine (0.034 mL, 0.198 mmol) were added and the solution was stirred at room temperature. After stirring 45 minutes, the reaction was complete. The reaction mixture was diluted with DMF and this crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 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: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (5.3 mg, 28.2% yield) as an off-white solid. 1H NMR (500 MHz, METHANOL-d4) δ 8.22-8.09 (m, 1H), 7.98 (dd, J=15.9, 1.5 Hz, 1H), 7.19-7.05 (m, 1H), 6.45-6.33 (m, 1H), 5.00 (t, J=4.0 Hz, 0.5H), 4.86 (t, J=4.2 Hz, 0.5H), 4.35-4.23 (m, 1.5H), 4.13 (d, J=10.9 Hz, 0.5H), 3.96-3.75 (m, 1.5H), 3.47-3.37 (m, 0.5H), 2.64 (s, 0.5H), 2.54 (s, 0.5H), 2.32 (s, 3H), 1.84-1.34 (m, 6H), 1.11-0.89 (m, 3H) fractional protons are due to the presence of amide rotomers; MS (ES+) m/z: 448.2 (M+H); LC retention time: 1.64 min (analytical LCMS Method H).

Provenance & Evidence