Diisopropylethylamine → 4-(((3S,4S)-1-(5-cyanothiazol-2-yl)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

Participants

Reaction Conditions

Reaction Steps

A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide from Step 5 of Example 266 (30 mg, 0.042 mmol), 2-chlorothiazole-5-carbonitrile (7.36 mg, 0.051 mmol) and diisopropylethylamine (0.052 mL, 0.297 mmol) in DMA (0.25 mL) was heated to 100° C. for 2 hr. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 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 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (5.3 mg, 0.024 mmol, 22% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.80 (d, J=2.0 Hz, 1H), 8.14 (s, 1H), 8.02 (dd, J=8.2, 2.2 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.69 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.14 (d, J=1.5 Hz, 1H), 5.07 (t, J=4.5 Hz, 1H), 4.58 (s, 2H), 4.01 (dd, J=10.9, 4.0 Hz, 1H), 3.97 (s, 2H), 3.83 (d, J=7.9 Hz, 2H), 3.46 (s, 4H), 2.79-2.66 (m, 1H), 1.77 (tq, J=14.6, 7.1 Hz, 2H), 1.04 (t, J=7.4 Hz, 3H). MS (ES+) m/z: 560.1 (M+H); LC retention time: 1.31 min (analytical LCMS Method H).

Provenance & Evidence