| 86% |
With tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct In 1,4-dioxane; water monomer at 60℃; for 16h; Inert atmosphere; |
2 Preparation of 6-Chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (C28-Int)
A mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2.00 g, 8.60 mmol), potassium phosphate (5.48 g, 25.80 mmol), 3-(trifluoromethoxy)phenylboronic acid (1.86 g, 9.30 mmol), water (0.77 mL, 43.00 mmol), and anhydrous 1,4-dioxane (30 mL) was degassed under argon for 30 min. To the mixture was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH2Cl2 (352 mg, 0.43 mmol) and the resulting mixture was heated to 60 °C for 16 h under an argon atmosphere. The resulting mixture was cooled to ambient temperature, filtered through Celite, and concentrated under reduced pressure to give a dark orange gum (3.6 g). The resulting residue was purified by automated flash column chromatography (n-hexane/ethyl acetate, 100:0 - 0:100, 100 g SiO2). The appropriate fractions were combined and concentrated under reduced pressure to give 6-chloro-3-(3- (trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine as a pale yellow solid (2.32 g, 86%). LCMS (UV, ESI) Rt = 20.37 min, [M-H]+ m/z = 313.9, 96% purity.1H NMR (600 MHz, d6 -DMSO): δ = 8.46 (1H, s), 8.34 (1H, d, J = 9.4 Hz), 8.17 (1H, s), 8.15 (1H, d, J = 8.0 Hz), 7.69 (1H, m), 7.48 (1H, d, J = 9.5 Hz), 7.42 (1H, d, J = 8.3 Hz). |
| 86% |
With tripotassium phosphate tribasic; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct In 1,4-dioxane; water monomer at 60℃; for 16h; Inert atmosphere; |
2 Preparation of 6-Chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (C28-Int)
A mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2.00 g, 8.60 mmol), potassium phosphate (5.48 g, 25.80 mmol), 3-(trifluoromethoxy)phenylboronic acid (1.86 g, 9.30 mmol), water (0.77 mL, 43.00 mmol), and anhydrous 1,4-dioxane (30 mL) was degassed under argon for 30 min. To the mixture was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH2Cl2 (352 mg, 0.43 mmol) and the resulting mixture was heated to 60 °C for 16 h under an argon atmosphere. The resulting mixture was cooled to ambient temperature, filtered through Celite, and concentrated under reduced pressure to give a dark orange gum (3.6 g). The resulting residue was purified by automated flash column chromatography (n-hexane/ethyl acetate, 100:0 - 0:100, 100 g SiO2). The appropriate fractions were combined and concentrated under reduced pressure to give 6-chloro-3-(3- (trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine as a pale yellow solid (2.32 g, 86%). LCMS (UV, ESI) Rt = 20.37 min, [M-H]+ m/z = 313.9, 96% purity.1H NMR (600 MHz, d6 -DMSO): δ = 8.46 (1H, s), 8.34 (1H, d, J = 9.4 Hz), 8.17 (1H, s), 8.15 (1H, d, J = 8.0 Hz), 7.69 (1H, m), 7.48 (1H, d, J = 9.5 Hz), 7.42 (1H, d, J = 8.3 Hz). |
| 30% |
With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In 1,4-dioxane; water monomer |
1.1
3-bromo-6-chloroimidazo[1,2-b]pyridazine was prepared according to procedures described in U.S. Pat. No. 7,750,007, which is hereby incorporated by reference in its entirety. To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (5 g, 21.5 mmol) and 3-(trifluoromethoxy)phenylboronic acid (4.43 g, 21.5 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (6.8 g, 64.5 mmol) and Pd(PPh3)4 (1.9 g, 2.58 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated, partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) for 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (3.2 g, with 63% purity, yield 30%) as a brown solid. |
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