1,4-DICHLOROPYRIDO[4,3-D]PYRIDAZINE

31384-08-4

14490-19-8

General procedure for the synthesis of 1,4-dichloropyrido[4,3-D]pyridazine from 1,4-dihydroxypyrido[4,3-D]pyridazine: pyrido[3,4-d]pyridazine-1,4-diol (1.83 g, 11.2 mmol) and phosphorus trichloride (8.4 mL, 89.7 mmol) were added to a round bottomed flask. N,N-diisopropylethylamine (DIPEA, 2.0 mL, 11.2 mmol) was slowly added to the reaction system. The resulting suspension was heated and refluxed at 100 °C for 1 h. The reaction solution was gradually transformed into a brown solution. Upon completion of the reaction, the excess phosphorus trichloride was removed by rotary evaporator. The residue was dissolved in dichloromethane (DCM) and added slowly and dropwise to a mixed system of ice-water mixture and saturated aqueous sodium bicarbonate (NaHCO3). The saturated NaHCO3 solution was continued to be added dropwise until the aqueous phase was neutral. The organic and aqueous phases were separated and the aqueous phase was further extracted with dichloromethane (500 mL). The organic phases were combined, dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure to afford the target product 1,4-dichloropyrido[3,4-d]pyridazine (1.74 g, 8.7 mmol, 78% yield). The structure of the product was confirmed by 1H NMR (400 MHz, CDCl3): δ 9.78 (d, J = 0.9 Hz, 1H), 9.27 (d, J = 5.7 Hz, 1H), 8.09 (dd, J = 5.7 Hz, 0.9 Hz, 1H). Mass spectrometry analysis (Method 2): retention time (RT) 1.16 min, electrospray positive ionization mode (ES+) m/z 209.0 [M + H]+.