Nitrogen → {3-[3-(4-Aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propyl}-methyl-carbamic acid isopropyl ester

Participants

Reaction Conditions

Reaction Steps

To a mixture of [3-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-propyl]-methyl-carbamic acid isopropyl ester (601.4 mg, 1.6 mmol), (4-(aminomethyl)phenyl)boronic acid hydrochloride [75705-21-4] (366.3 mg, 2.0 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (1.1 g, 4.9 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with dichloromethane [95464-05-4] (138.7 mg, 0.2 mmol) contained in a 50 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (12 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 17 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) purified by preparative RP-HPLC. Purified chromatography fractions were combined and partitioned between aqueous saturated sodium bicarbonate and ethyl acetate. The organic extract dried (CaSO4) and evaporated to provide {3-[3-(4-aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-propyl}-methyl-carbamic acid isopropyl ester as 19.4 mg of clear yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.12 (br. s., 2H) 1.17-1.28 (m, 4H) 1.84-1.98 (m, 2H) 2.90 (s, 2H) 3.10-3.21 (m, 1H) 3.32-3.43 (m, 3H) 3.88 (s, 2H) 4.78-4.87 (m, 4H) 6.69 (d, J=9.60 Hz, 1H) 7.45 (d, J=8.34 Hz, 2H) 7.61 (d, J=9.60 Hz, 1H) 7.69-7.75 (m, 1H) 8.12 (dd, J=8.21, 2.65 Hz, 2H). 13C NMR (100 MHz, METHANOL-d4) δ ppm 22.58, 37.39, 40.24, 46.39, 70.29, 110.81, 114.20, 125.95, 126.19, 127.75, 127.85, 128.87, 129.41, 129.65, 129.73, 130.34, 138.67, 141.99, 155.32. LRMS (ESI) m/z 397.3 [(M+H)]+, calc'd for C21H28N6O2: 396.50.

Provenance & Evidence