Reaction Steps
To a mixture of tert-butyl 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-1,4-diazepane-1-carboxylate (329.9 mg, 0.8 mmol), (3-methoxy pyridin-4-yl)boronic acid monohydrate [1072952-50-1] (153.6 mg, 1.0 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (384.1 mg, 1.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (69.2 mg, 0.1 mmol) contained in a 50 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (25 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 6 h then cooled and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to afford a brown solid which was purified by preparative RP-HPLC to provide 4-[3-(3-methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as 79.5 mg of off white powder, mp. 115-116° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotomers present) 1.01 (s, 4H) 1.20 (s, 4H) 1.91 (s, 2H) 2.51 (dt, J=3.60, 1.86 Hz, 2H) 3.27-3.35 (m, 4H) 3.57 (br. s., 1H) 3.64 (s, 1H) 3.70 (br. s., 2H) 3.81 (d, J=16.67 Hz, 2H) 4.02 (s, 3H) 7.19 (d, J=9.85 Hz, 1H) 7.93 (s, 1H) 8.11 (d, J=8.59 Hz, 1H) 8.32 (d, J=5.05 Hz, 1H) 8.49-8.54 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm (rotomers present) 13.89, 22.03, 24.66, 24.75, 27.49, 27.74, 31.20, 44.27, 44.96, 45.60, 47.99, 48.26, 48.39, 56.31, 78.25, 78.41, 109.66, 109.87, 119.88, 120.03, 120.27, 124.50, 126.00, 126.08, 134.46, 135.39, 135.52, 136.92, 141.96, 150.98, 152.56, 152.65, 154.01, 154.34. LRMS (ESI) m/z 425.2 [(M+H)]+, calc'd for C22H28N6O3: 424.51.
