6-bromo-1-fluoronaphthalen-2-ol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline (prepared as described in WO 03/33472)(0.465 mg, 1.93 mmol), 6-bromo-1-fluoro-naphthalen-2-ol (Example 3a) (0.65 mg, 1.93 mmol) and DMAP (0.235 mg, 1.93 mmol, Aldrich) in toluene (in a microwave tube) was heated in a microwave oven (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with brine (2×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (40% to 100% EtOAc in hexanes) to give the title compound as an orange foam. MS (ESI, pos. ion) m/z: 541.1 (M+1). Mass Calc'd for C27H26BrFN2O4: 540.11. The mixture was cooled to RT The solution was washed with brine (2×10 mL) dried over Na2SO4 concentrated in vacuo The residue was further purified with silica gel column chromatography (40% to 100% EtOAc in hexanes)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-6,7-dimethoxy-quinoline (prepared as in Example 1, Step b)(371 mg, 1.66 mmol), 6-bromo-1-fluoro-naphthalen-2-ol (Step a, 400 mg, 1.66 mmol) and DMAP (203 mg, 1.66 Aldrich) in toluene (in a microwave tube) was heated in a microwave oven (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with 10 mL of brine twice, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (40-100% EtOAc in hexanes) to give title compound as a white solid. MS (ESI, pos. ion) m/z: 428.0 (M+1). Mass Calc'd for C21H15BrFNO3: 427.02. The mixture was cooled to RT The solution was washed with 10 mL of brine twice dried over Na2SO4 concentrated in vacuo The residue was further purified with silica gel column chromatography (40-100% EtOAc in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-bromo-naphthalen-2-ol (5 g, 22.4 mmol, Aldrich) in dry DMF (50 mL, Aldrich) was added N-fluorobenzene sulfonimide (21.9 g, 67.2 mmol, Aldrich). The reaction was stirred at RT for 48 h. The volatile portion was removed in vacuo and the residue was purified by silica gel chromatography (CHCl3) to give title compound as a yellow solid. MS (ESI, neg. ion) m/z: 240.0 (M−1). Mass Calc'd for C10H6BrFO: 239.96. The volatile portion was removed in vacuo the residue was purified by silica gel chromatography (CHCl3)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline (prepared as described in WO 03/33472) (0.465 mg, 1.93 mmol), 6-bromo-1-fluoro-naphthalen-2-ol (Example 3a) (0.65 mg, 1.93 mmol) and DMAP (0.235 mg, 1.93 mmol, Aldrich) in toluene (in a microwave tube) was heated in a microwave oven (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with brine (2×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (40% to 100% EtOAc in hexanes) to give the title compound as an orange foam. MS (ESI, pos. ion) m/z: 541.1 (M+1). Mass Calc'd for C27H26BrFN2O4: 540.11. The mixture was cooled to RT The solution was washed with brine (2×10 mL) dried over Na2SO4 concentrated in vacuo The residue was further purified with silica gel column chromatography (40% to 100% EtOAc in hexanes)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-6,7-dimethoxy-quinoline (prepared as in Example 1, Step b)(371 mg, 1.66 mmol), 6-bromo-1-fluoro-naphthalen-2-ol (Step a, 400 mg, 1.66 mmol) and DMAP (203 mg, 1.66 Aldrich) in toluene (in a microwave tube) was heated in a microwave oven (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with 10 mL of brine twice, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (40-100% EtOAc in hexanes) to give title compound as a white solid. MS (ESI, pos. ion) m/z: 428.0 (M+1). Mass Calc'd for C21H15BrFNO3: 427.02. The mixture was cooled to RT The solution was washed with 10 mL of brine twice dried over Na2SO4 concentrated in vacuo The residue was further purified with silica gel column chromatography (40-100% EtOAc in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-bromo-naphthalen-2-ol (5 g, 22.4 mmol, Aldrich) in dry DMF (50 mL, Aldrich) was added N-fluorobenzene sulfonimide (21.9 g, 67.2 mmol, Aldrich). The reaction was stirred at RT for 48 h. The volatile portion was removed in vacuo and the residue was purified by silica gel chromatography (CHCl3) to give title compound as a yellow solid. MS (ESI, neg. ion) m/z: 240.0 (M−1). Mass Calc'd for C10H6BrFO: 239.96. The volatile portion was removed in vacuo the residue was purified by silica gel chromatography (CHCl3)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-bromonaphthalen-2-ol (2.23 g, 10.0 mmol) in CH3CN (50 mL) was added Selectfluor (4.20 g, 12.0 mmol). The reaction mixture was heated at 60° C. overnight and concentrated. The residue was partitioned between water (50 mL) and EtOAc (100 mL). The aqueous phase was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 6-bromo-1-fluoronaphthalen-2-ol using ethyl acetate and hexanes as solvents (2.0 g, 83% yield). concentrated The residue was partitioned between water (50 mL) and EtOAc (100 mL) The aqueous phase was separated extracted with ethyl acetate The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The residue was purified by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Followed the coupling procedure described in Example 29 starting from 6-bromo-1-fluoronaphthalen-2-ol (Intermediate 13) and methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 12.90 (b, 1H), 10.17 (b, 1H), 7.84-7.97 (m, 4H), 7.70 (d, 1H), 7.54 (d, 1H), 7.41 (d, 1H), 7.30 (t, 1H), 2.33 (s, 3H). MS (ESI): m/z=295.25 [MA]−.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Followed the coupling procedure described in Example 29 starting from 6-bromo-1-fluoronaphthalen-2-ol (Intermediate 13) and 4-borono-3-fluorobenzoic acid. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 13.32 (b, 1H), 10.28 (b, 1H), 8.14 (s, 1H), 7.98 (d, 1H), 7.78 (d, 1H), 7.73-7.76 (m, 4H), 7.32 (t, 1H), MS (ESI): m/z=299.40 [M−1]−.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Followed the coupling procedure described in Example 29 starting from 6-bromo-1-fluoronaphthalen-2-ol (Intermediate 13) and 4-boronobenzoic acid. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 13.04 (b, 1H), 10.23 (b, 1H), 8.29 (s, 1H), 7.91-8.01 (m, 7H), 7.74 (d, 1H). MS (ESI): m/z=281.26 [M−1]−.