S(=O)(=O)(O)O.[CH2:6]([N:8]1[C:12]2[N:13]=[N:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:11]=2[N:10]=[CH:9]1)[CH3:7].[Br:24]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(O)[O-].[Na+].[OH-].[Na+]>CCOC(C)=O>[Br:24][C:19]1[CH:18]=[C:17]([C:16]2[C:11]3[N:10]=[CH:9][N:8]([CH2:6][CH3:7])[C:12]=3[N:13]=[N:14][CH:15]=2)[CH:22]=[CH:21][C:20]=1[F:23]Concentrated sulphuric acid (66 g, 0.67 mol) was carefully added to 7-ethyl-4-(4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 9, 2.3 g, 9.5 mmol) surrounded by an ice bath, and the resultant reaction mixture was gently stirred at room temperature until a homogeneous solution was observed. To this solution was added 1,3-dibromo-5,5-dimethylhydantoin (2.7 g, 9.5 mmol) portion-wise, and stirring was continued at 0° C. for 2 hours. The reaction mixture was poured carefully into aqueous sodium bisulphite (200 mL), and then basified with an aqueous sodium hydroxide solution (2 M) to pH=8 keeping the temperature below 20° C. EtOAc (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phases were washed with saturated brine solution, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether:CH2Cl2 1:1 followed by trituration with EtOAc to afford the title compound as a white solid in 41% yield, 1.25 g.
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