Potassium Phosphate, Tribasic → 4-((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-ylamino)-6-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazine-3-carboxamide

Participants

Reaction Conditions

Reaction Steps

A solution of 6-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.045 mmol) in 1,4-dioxane (0.3 mL), was added (4-methoxyphenyl)boronic acid (10.2 mg, 0.07 mmol), [1,1′-(diphenylphosphino)ferrocene]-dichloropalladium (II) (3.27 mg, 4.5 μmol), potassium phosphate (0.08 mL, 0.16 mmol). The reaction vial was purged with N2, sealed and heated at 85° C. overnight. 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: 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 (9 mg 42% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.19 (d, J=7.0 Hz, 1H), 7.95 (d, J=7.0 Hz, 1H), 7.72-7.65 (m, 2H), 7.28 (d, J=14.5 Hz, 1H), 7.02-6.95 (m, 2H), 5.23-5.11 (m, 1H), 4.57 (dd, J=10.1, 7.0 Hz, 1H), 4.32-4.24 (m, 1H), 4.24-4.16 (m, 1H), 4.14-4.06 (m, 1H), 3.94-3.88 (m, 1H), 3.86 (s, 3H), 3.78-3.71 (m, 1H), 3.60-3.53 (m, 2H), 3.40 (s, 3H), 1.79-1.52 (m, 3H), 1.45-1.35 (m, 1H); MS (ES+) m/z: 475.2 (M+H); LC retention time: 3.49 min (analytical HPLC Method B).

Provenance & Evidence