N,N'-Dimethylethylenediamine → HCID 88948489, compound

Participants

Reaction Conditions

Reaction Steps

A mixture of 6-bromo-4-(1-(6-cyanopyridazin-3-yl)-3,3-dimethylpiperidin-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 4 of Example 1 (20 mg, 0.043 mmol), 2,2,2-trifluoroacetamide (9.6 mg, 0.085 mmol), copper(I) iodide (1.6 mg, 8.52 μmol), potassium carbonate (11.8 mg, 0.085 mmol) and N1,N2-dimethylethane-1,2-diamine (10 μl, 0.094 mmol) in dioxane (0.5 mL) was pumped and backfilled with nitrogen twice. The reaction vial was sealed and stirred at 90-95° C. for 16 h. LCMS analysis showed the reaction was ˜40% complete. The 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: 15-100% 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. The material was further 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 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 20-55% B over 25 minutes, then a 15-minute hold at 55% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound, assumed as TFA salt (4 mg, 15% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.11 (1 H, s), 7.96 (1 H, d, J=1.66 Hz), 7.55-7.58 (1 H, m), 7.15-7.21 (2 H, m), 4.22 (1 H, d, J=13.04 Hz), 4.17 (1 H, dd, J=10.40, 3.75 Hz), 3.42-3.51 (1 H, m), 3.20 (1 H, d, J=13.87 Hz), 2.24 (1 H, dd, J=13.87, 3.61 Hz), 1.85-1.94 (1 H, m), 1.11 (3 H, s), 1.10 (3 H, s); MS (ES+) m/z: 502.13 (M+H); LC retention time: 2.225 min (analytical HPLC Method C).

Provenance & Evidence