Tetrahydrofuran → 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one

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To a suspension of 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid (7) (1.00 g, 3.15 mmol) in 10:1 THF:H2O (11 mL), stirred at 55° C., was added lithium acetate dihydrate (67 mg, 0.66 mmol). The mixture was stirred at 55° C. and treated with NBS (1.51 g, 8.48 mmol) in three equal portions at 30 min intervals. After addition of NBS was complete, the reaction mixture was stirred an additional 1 h at 55° C. In a separate flask, a suspension of 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid (7) (0.92 g, 2.89 mmol) in 10:1 THF:H2O (10 mL) stirred at 55° C. was treated with lithium acetate dihydrate (62 mg, 0.61 mmol) followed by NBS (1.39 g, 7.80 mmol) under the same conditions. Upon complete reaction, the two reaction mixtures were combined, diluted with water, and extracted with CH2Cl2. The combined organic layers were washed with 20% THF in water, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography [eluting with a gradient of 10-40% B in A where the eluents were: A=CH2Cl2; B=1:49.5:49.5 MeOH:EtOAc:CH2Cl2] to give 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one as a yellow solid. MS (ESI, pos. ion) m/z: 350, 352 (M+1, M+3).

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