Cyclopropylamine → HCID 178522327, Verbindung

Temperatur

80 °C

To a ˜1:1 mixture of 6,8-dichloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (600 mg, 1.84 mmol) and DIEA (0.482 mL, 2.76 mmol) in THF (10.00 mL) was added cyclopropanamine (158 mg, 2.76 mmol), and the reaction was heated at 80° C. in a sealed tube apparatus for 2 hrs. The reaction mixture was concentrated, dissolved in NMP (5 mL), and trans-4-aminocyclohexanol (4238 mg, 36.8 mmol) was added. The reaction mixture was heated at 100° C. for 24 hrs, and purified using preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) with 40% to 100% MeOH (0.1% TFA) in water (0.1% TFA)) to isolate the title compound, 8-(cyclopropylamino)-N-(2-fluoro-4-pyridinyl)-6-((trans-4-hydroxycyclohexyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (179 mg, 0.421 mmol, 22.87% yield), as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.722 (M+H=426.15). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, s), 8.19 (1H, d, J=5.52 Hz), 7.96 (1H, s), 7.60 (1H, s), 7.41-7.57 (2H, m), 6.94 (1H, d, J=7.28 Hz), 5.99 (1H, s), 4.60 (1H, d, J=4.02 Hz), 3.67 (1H, br. s.), 3.47 (1H, br. s.), 2.08 (2H, br. s.), 1.88 (2H, d, J=2.76 Hz), 1.15-1.45 (4H, m), 0.70-0.89 (2H, m), 0.52-0.71 (2H, m).

1. concentrationThe reaction mixture was concentrated
2. dissolutiondissolved in NMP (5 mL)
3. temperatureThe reaction mixture was heated at 100° C. for 24 hrs
4. custompurified

ORD-Eintrag

ord-2a9d4c314f9543dc987c189c9db5d61c

Quelldatensatz

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08389527B2