N,N'-Dimethylethylenediamine → HCID 68350492, compound

Participants

Reaction Conditions

Reaction Steps

A mixture of (R)-6-bromo-4-((1-(4-cyanophenyl)-3,3-dimethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.039 mmol), (S)-tert-butyl (2-oxopyrrolidin-3-yl)carbamate (21.6 mg, 0.108 mmol), copper(I) iodide (1.5 mg, 7.70 mmol), potassium carbonate (16.0 mg, 0.116 mmol) in dioxane (0.5 mL) was pumped under vacuum and backfilled with nitrogen twice. N1,N2-dimethylethane-1,2-diamine (8.3 μl, 0.077 mmol) was added. The reaction tube was sealed and heated at 100° C. for 17 h. The mixture was diluted with a 1:1 mixture of methanol-dichloromethane (2 mL) and filtered. The filtrate was concentrated to give crude product (48.3 mg) as brown solid. Part of the material (15.6 mg) was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×100 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water; Mobile Phase B: acetonitrile; Buffer: 20-mM ammonium acetate; Gradient: 15-100% B over 10.9 minutes, then a 4.0 minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give tert-butyl ((S)-1-(3-carbamoyl-4-(((R)-1-(4-cyanophenyl)-3,3-dimethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-2-oxopyrrolidin-3-yl)carbamate (4.4 mg, 20% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.11 (s, 1H), 7.79 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.27 (s, 1H), 6.94 (d, J=8.9 Hz, 2H), 4.41 (t, J=9.4 Hz, 1H), 4.09 (dd, J=10.2, 3.7 Hz, 1H), 3.91-3.72 (m, 3H), 3.57 (d, J=12.9 Hz, 1H), 3.25-3.16 (m, 1H), 2.95 (d, J=13.4 Hz, 1H), 2.66-2.57 (m, 1H), 2.25-2.07 (m, 2H), 1.96-1.84 (m, 1H), 1.44 (s, 9H), 1.16 (s, 3H), 1.08 (s, 3H); MS (ES+) m/z: 587.1 (M+H); LC retention time: 1.78 min (analytical LCMS Method I).

Provenance & Evidence