1,3-Dibromo-5-methoxybenzene

solid

3, 5-Dibromonitrobenzene (21.07 g, 75 mmol), freshly powdered potassium hydroxide (7.57 g, 135 mmol) and tetrabutylammonium bromide (2.42 g, 7.5 mmol) were suspended in tetramethyl urea (80 mL). To the resulting brown slurry was slowly added a solution of methanol (4.81 g, 6.09 mL, 150 mmol) in 20 mL of tetramethyl urea at room temperature over a period of 15 minutes. The mixture was stirred for 24 hours at room temperature then poured on ice (150 g) and was extracted with t-butyl methyl ether (3.x.250 mL). The combined organics were dried over magnesium sulfate and concentrated to give the crude product which was distilled (124° C., 10 Torr) to provide 16.74 g (84percent) of 3, 5-dibromoanisole as a pale yellow solid.(a) 3, 5-Dibromoanisole. 3, 5-Dibromonitrobenzene (21.07 g, 75 mmol), freshly powdered potassium hydroxide (7.57 g, 135 mmol) and tetrabutylammonium bromide (2.42 g, 7.5 mmol) were suspended in tetramethyl urea (80 mL). To the resulting brown slurry was slowly added a solution of methanol (4.81 g, 6.09 mL, 150 mmol) in 20 mL of tetramethyl urea at room temperature over a period of 15 minutes. The mixture was stirred for 24 hours at room temperature then poured on ice (150 g) and was extracted with t-butyl methyl ether (3.x.250 mL). The combined organics were dried over magnesium sulfate and concentrated to give the crude product which was distilled (124° C., 10 Torr) to provide 16.74 g (84percent) of 3, 5-dibromoanisole as a pale yellow solid.0294] (a) 3, 5-Dibromoanisole. 3, 5-Dibromonitrobenzene (21.07 g, 75 mmol), freshly powdered potassium hydroxide (7.57g, 135 mmol) and tetrabutylammonium bromide (2.42 g, 7.5 mmol) were suspended in tetramethyl urea (80 mL). To the resulting brown slurry was slowly added a solution of methanol (4.81 g, 6.09 mL, 150 mmol) in 20 mL of tetramethyl urea at room temperature over a period of 15 minutes. The mixture was stirred for 24 hours at room temperature then poured on ice (150 g) and was extracted with t-butyl methyl ether (3x250 mL). The combined organics were dried over magnesium sulfate and concentrated to give the crude product which was distilled (124Step 1: To a 500 mL round bottom flask was added 3, 5-dibromofluorobenzene (8) (20.0 g, 0.08 mol, 1 eq.) And anhydrous DMF (350 mL). To a round bottom flask was slowly added sodium methoxide (5.2 g , 0.09 mol, 1.2 eq.), Stir at room temperature overnight, Then add 5percent HCl to neutralize, Stop the reaction. CH2Cl2 extraction (50 mL x 3), The organic phase was washed with distilled water (50 mL x 3) The organic phase was dried over anhydrous magnesium sulfate, The magnesium sulfate was removed by filtration, The solvent was removed by flash evaporation to give a pale yellow solid, Silica gel column chromatography (eluent: petroleum ether), A white solid was obtained 30 g, Yield 95percent.To a solution of 2, 6-dibromo-4-methoxyphenylamine (3 g, 10.67 mmol, 1 eq) in 10 ml of toluene cooled at 0° C. are added 6.6 ml of concentrated sulfuric acid and 17.5 ml of H3, 5-Dibromoanisole (15.57 g, 58.5 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) were suspended in 48percent hydrobromic acid (100 mL) and refluxed for 3 days. After cooling to room temperature the reaction mixture was extracted with methylene chloride (3.x.60 mL). The combined organic layers were washed with water, dried over magnesium sulfate, and evaporated. The crude product was filtered over a pad of silica gel (ethyl acetate/heptane 10:1). After removal of the solvent, 14.23 g (97percent of 3, 5-dibromophenol was obtained as pale brown needles.(b) 3, 5-Dibromophenol. 3, 5-Dibromoanisole (15.57 g, 58.5 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) were suspended in 48percent hydrobromic acid (100 mL) and refluxed for 3 days. After cooling to room temperature the reaction mixture was extracted with methylene chloride (3.x.60 mL). The combined organic layers were washed with water, dried over magnesium sulfate, and evaporated. The crude product was filtered over a pad of silica gel (ethyl acetate/heptane 10:1). After removal of the solvent, 14.23 g (97percent of 3, 5-dibromophenol was obtained as pale brown needles.[0295] (b) 3, 5-Dihromophenol. 3, 5-Dibromoanisole (15.57 g, 58.5 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) were suspended in 48percent hydrobromic acid (100 mL) and refluxed for 3 days. After cooling to room temperature the reaction mixture was extracted with methylene chloride (3x60 mL). The combined organic layers were washed with water, dried over magnesium sulfate, and evaporated. The crude product was filtered over a pad of silica gel (ethyl acetate/heptane 10:1). After removal of the solvent, 14.23 g (97percent of 3, 5-dibromophenol was obtained as pale brown needles.To a 250 mL two-necked flask was added Succinic acid mono-{3-[4-chloro-3-(3, 5-dicyano-phenoxy)-2-fluoro-benzyl]-4-methyl-5-oxo-4, 5-dihydro-[1, 2, 4]triazol-1-ylmethyl} ester was prepared in a similar manner except steps 1 and 2 were omitted and 3, 5-dibromophenol was used in the place of 3-bromo-5-chlorophenol in step 3 to afford I-4: mp 141.6-143.3° C., MS (ES-): m/z 512, 1H NMR (d6-DMSO, 300 MHz) delta 12.2 (br.s, 1H), 8.23 (t, J=1.2 Hz, 1H), 7.95 (d, J=1.2 Hz, 2H), 7.52 (dd, J=1.5, 8.6 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 5.63 (s, 2H), 4.09 (s, 2H), 3.14 (s, 3H) 2.52-2.43 (m, 4H). Anal. Calcd for C23H17FClN5O6: C, 53.76; H, 3.33; N, 13.63. Found: C, 53.68; H, 3.47; N, 13.35. 3, 5-Dibromophenol was prepared from