3-(bromomethyl)-1,2-difluoro-4-methoxybenzene

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

Procedure: A suspension of 4-fluoro-3-hydroxybenzoic acid (0.19 g), 2,3-difluoro-6-methoxybenzyl bromide (0.6 g) and potassium carbonate (0.5 g) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (6 mL). To the solution were added methanol (3 mL), water (3 mL) and lithium hydroxide-monohydrate (0.5 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid (15 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in a mixed solvent (n-hexane/ethyl acetate=4/1) and collected by filtration, and dried under reduced pressure to give 4-fluoro-3-(2,3-difluoro-6-methoxybenzyloxy)benzoic acid (0.31 g). This material was dissolved in 1,4-dioxane (4 mL). To the solution were added triethylamine (0.41 mL) and diphenylphosphoryl azide (0.21 mL), and the mixture was stirred at room temperature for 1 hour. Then the mixture was heated for reflux for 4 hours. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1−1/1) to give crude product. To the crude product was added methylene chloride, and the insoluble material was removed by filtration. the resulting mixture was extracted with diethyl ether The extract was washed with water and brine successively dried over anhydrous sodium sulfate The solvent was removed under reduced pressure the residue was dissolved in tetrahydrofuran (6 mL) To the solution were added methanol (3 mL), water (3 mL) and lithium hydroxide-monohydrate (0.5 g) the mixture was stirred at room temperature for 1 hour To the reaction mixture was added 1 mol/L hydrochloric acid (15 mL) the resulting mixture was extracted with ethyl acetate The extract was washed with water and brine successively dried over anhydrous sodium sulfate The solvent was removed under reduced pressure collected by filtration dried under reduced pressure

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

Procedure: To a suspension of 4-fluoro-2-methoxy-5-nitroaniline (0.37 g) and potassium carbonate (0.36 g) in N,N-dimethylformamide (10 mL) was added 2,3-difluoro-6-methoxybenzyl-bromide (0.47 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 5-fluoro-2-(2,3-difluoro-6-methoxybenzylamino)-4-nitroanisole (0.32 g). This material was dissolved in N,N-dimethylformamide (9.3 mL). To the solution were added sodium hydride (55%, 45 mg) and methyl iodide (0.18 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (4 mL)-tetrahydrofuran (4 mL). To the solution were added nickel(II) bromide (11 mg) and sodium borohydride (0.11 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (0.17 g). the resulting mixture was extracted with ethyl acetate The extract was washed with water and brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1)

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

Procedure: The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(bromomethyl)-3,4-difluoro-1-methoxybenzene in a manner similar to that described in Example 25 as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.64 (d, J=7.0 Hz, 1 H), 7.43-7.38 (m, 1 H), 7.34 (d, J=7.4 Hz, 2 H), 7.12 (d, J=3.5 Hz, 1 H), 7.00 (dd, J=9.2, 10.1 Hz, 1 H), 6.73 (dd, J=6.4, 11.9 Hz, 1 H), 6.24 (d, J=3.5 Hz, 1 H), 5.54 (s, 1 H), 5.48 (d, J=6.0 Hz, 2 H), 3.86 (s, 3 H), 2.78 (s, 3 H), 2.47 (s, 3 H), 0.95 (s, 9 H); LCMS (m/z) ES+=509 (M+1).

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: See FIG. 17(a). In a 50 mL round-bottomed flask N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.1 g, 0.48 mmol) was DMF (10 mL) to give a colourless suspension. the reaction mixture was cooled to 0° C. and potassium carbonate (0.200 g, 1.45 mmol) and 2-(bromomethyl)-3,4-difluoro-1-methoxybenzene (0.114 g, 0.48 mmol) was added then the RM was stirred at 80° C. for 4 h. The reaction was monitored by LCMS. DMF was concentrated under vacuao, added water and extracted with DCM. The combined organic layer was washed with brine, dried over sodium sulphate, filtered and evaporated to give crude product. The crude material was purified on reverse phase preparative HPLC system to get 1-(2,3-difluoro-6-methoxybenzyl)-N-(2-fluoroethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.060 g, 34.2%). ES+MS m/z: 364 (M+1) 1H NMR (DMSO-d6, 300 MHZ): δ ppm 8.90 (br. s., 1 H ), 8.50 (d, J=4.3 Hz, 1 H ), 8.02-8.15 (m, 2 H ), 7.30-7.52 (m, 2 H ), 6.92 (d, J=8.7 Hz, 1 H ), 5.53 (s, 2 H ), 4.63 (t, J=4.4 Hz, 1 H ), 4.47 (t, J=4.8 Hz, 1 H ), 3.86 (s, 3 H ), 3.74 (d, J=5.3 Hz, 1 H ), 3.65 (d, J=5.3 Hz, 1 H ). DMF was concentrated under vacuao added water extracted with DCM The combined organic layer was washed with brine dried over sodium sulphate filtered evaporated to give crude product The crude material was purified on reverse phase preparative HPLC system

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

Procedure: To a solution of 4-chloro-5-nitrocatechol (10.4 g) in N,N-dimethylformamide (55 mL) was added sodium hydride (55%, 5.04 g) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added N,N-dimethylformamide (11 mL), followed by adding a solution of 2,3-difluoro-6-methoxy-benzyl bromide (14.3 g) in N,N-dimethylformamide (22 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, and then stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water. The mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=7/3−1/1) to give the title compound (18.5 g). cooling cooling the mixture was stirred at the same temperature for 10 minutes stirred at room temperature for 1.5 hours the resulting mixture was extracted with ethyl acetate The extract was washed with water and brine dried over anhydrous sodium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=7/3−1/1)

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

Procedure: A suspension of 4-fluoro-3-hydroxybenzoic acid (0.19 g), 2,3-difluoro-6-methoxybenzyl bromide (0.6 g) and potassium carbonate (0.5 g) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (6 mL). To the solution were added methanol (3 mL), water (3 mL) and lithium hydroxide-monohydrate (0.5 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid (15 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in a mixed solvent (n-hexane/ethyl acetate=4/1) and collected by filtration, and dried under reduced pressure to give 4-fluoro-3-(2,3-difluoro-6-methoxybenzyloxy)benzoic acid (0.31 g). This material was dissolved in 1,4-dioxane (4 mL). To the solution were added triethylamine (0.41 mL) and diphenylphosphoryl azide (0.21 mL), and the mixture was stirred at room temperature for 1 hour. Then the mixture was heated for reflux for 4 hours. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1−1/1) to give crude product. To the crude product was added methylene chloride, and the insoluble material was removed by filtration. the resulting mixture was extracted with diethyl ether The extract was washed with water and brine successively dried over anhydrous sodium sulfate The solvent was removed under reduced pressure the residue was dissolved in tetrahydrofuran (6 mL) To the solution were added methanol (3 mL), water (3 mL) and lithium hydroxide-monohydrate (0.5 g) the mixture was stirred at room temperature for 1 hour To the reaction mixture was added 1 mol/L hydrochloric acid (15 mL) the resulting mixture was extracted with ethyl acetate The extract was washed with water and brine successively dried over anhydrous sodium sulfate The solvent was removed under reduced pressure collected by filtration dried under reduced pressure