Potassium Phosphate, Tribasic → 4-((3R,4S)-1-(5-cyanopyrimidin-2-yl)-4-methoxypyrrolidin-3-ylamino)-6-(4-(cyclopropylcarbamoyl)phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamide

関与物質

反応条件

反応手順

A solution of 6-bromo-4-(((3R,4S)-1-(5-cyanopyrimidin-2-yl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.022 mmol) in 1,4-dioxane (0.5 mL), was added [1,1′-[bis(diphenylphosphino)ferrocene]-dicholorpalladium (II) (1.601 mg, 2.187 μmol), [4-(cyclopropylcarbamoyl)phenyl]-boronic acid (6.73 mg, 0.033 mmol) and potassium phosphate (2M, 0.033 mL, 0.066 mmol). The reaction vial was purged with nitrogen, sealed and heated at 140° C. for 1 h. 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 (4.2 mg, 35% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.57 (br. s., 1H), 8.51 (d, J=3.0 Hz, 1H), 8.13 (d, J=3.5 Hz, 1H), 7.95 (br. s., 1H), 7.87-7.75 (m, 2H), 7.73-7.66 (m, 2H), 7.62-7.55 (m, 2H), 7.18 (br. s., 1H), 5.09 (br. s., 1H), 4.33-4.22 (m, 2H), 4.02-3.94 (m, 1H), 3.93-3.84 (m, 1H), 3.77-3.69 (m, 1H), 3.52 (d, J=3.5 Hz, 3H), 2.89-2.80 (m, 1H), 0.80 (m, 4H). MS (ES+) m/z: 538.22 (M+H); LC retention time: 1.31 min (analytical HPLC Method I).

情報源と証拠