4-bromo-2-chloro-1-iodobenzene

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

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 6-amino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (6) (8.00 g, 34.16 mmol) and cesium carbonate (22.48 g, 68.31 mmol) in anhydrous anisole (76 mL) under nitrogen was added 4-bromo-2-chloroiodobenzene (1.60 g, 1.10 equiv., 4.88 mmol). The preformed catalyst, as prepared above, was then added to the mixture to provide a dark brown suspension, which was heated at 100±2° C., with stirring at 350 rpm. The reaction was monitored by HPLC analysis. After 41 hours, no 6-amino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (6) remained. The reaction mixture was cooled to about 80° C. and 1M sulfuric acid (40.99 mL 40.99 mmol) was added. Gas evolution was observed after 10 minutes and the rate of addition was controlled to moderate the effervescence. At the end of the addition the pH was between 7 and 8. Additional sulfuric acid (1M, 10.25 mL, 10.25 mmol) was then added to give mobile slurry with a pH of 0. The mixture was diluted with anisole (20 mL) and Celatom FW-14 filter agent was added. It was then filtered at about 80° C. through a water-wet pad of Celatom FW-14 filter agent and the cake was washed with anisole (1×40 mL+3×20 mL), then water (10 mL). The lower aqueous layer was separated and discarded and the organic layer was washed with 10% aqueous NaCl solution (2×40 mL). This was added to a sodium hydroxide (5.46 g, 68.3 mmol) in methanol (24 mL) and the mixture was heated at 65° C. with stirring. After 17.5 hours HPLC analysis indicated that the hydrolysis of the ester was complete and the slurry was cooled to 15° C., then filtered on a sinter. The solid was washed with water (4×24 mL), MTBE (24 mL), and acetonitrile (2×25 mL) and then dried at 45° C. in a vacuum oven to provide 11.07 g of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (7) as a fine pale brown solid (assay 93.7% by 1H NMR), actual wt 10.37 g (72.2% yield). 1H NMR (400 MHz, d6 DMSO) δ 3.85 (3H, s, NMe), 6.53 (1H, dd, J 9, 7, Ar—H), 7.27 (1H, dd, J 9, 2.5, Ar—H), 7.56 (1H, d, J 9, Ar—H), 7.97 (1H, s, Ar—H), 8.20 (1H, s, Ar—H), 11.5 (1H, s, CO2H). 13C NMR (100 MHz, d6 DMSO) δ 31 (CH3), 108 (CH, d, J 2), 109 (CH), 117 (C, d, J 6), 122 (C), 124 (C, d, J 7), 127 (C), 130 (C), 131 (C), 132 (C, d, J 9), 133 (C, d, J 11), 141 (C), 145 (CF, d, J 252), 146 (CH), 170 (C═O). The preformed catalyst, as prepared above, was then added to the mixture to provide a dark brown suspension, which The reaction mixture was cooled to about 80° C. Gas evolution was observed after 10 minutes the rate of addition At the end of the addition the pH was between 7 and 8 to give mobile slurry with a pH of 0 filter agent was added It was then filtered at about 80° C. through a water-wet pad of Celatom FW-14 filter agent the cake was washed with anisole (1×40 mL+3×20 mL) The lower aqueous layer was separated the organic layer was washed with 10% aqueous NaCl solution (2×40 mL) the mixture was heated at 65° C. with stirring the slurry was cooled to 15° C. filtered on a sinter The solid was washed with water (4×24 mL), MTBE (24 mL), and acetonitrile (2×25 mL) dried at 45° C. in a vacuum oven

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

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

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-2-chloro-1-iodo-benzene (10.0 g, 31.5 mmol) in THF (120 ml) was added 2 M solution of isopropylmagnesium chloride in THF (17.3 ml, 34.60 mmol) at −65° C. The reaction mixture was stirred at −40° C. for 20 min. After 2-chloro-5-methoxy-benzaldehyde (5.5 g, 32.20 mmol) was added, the reaction mixture was warmed to room temperature and stirred overnight. Then the solution was quenched with saturated aqueous solution of NH4Cl. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude material was purified by chromatography (petroleum ether/CH2Cl2 1:1) to provide title compound as a yellowish oil. the reaction mixture was warmed to room temperature stirred overnight Then the solution was quenched with saturated aqueous solution of NH4Cl The aqueous phase was extracted twice with diethyl ether The combined organic phases were dried over MgSO4 concentrated in vacuo The crude material was purified by chromatography (petroleum ether/CH2Cl2 1:1)

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

Procedure: The reaction was run under an argon atmosphere using dry glassware. 4-Bromo-2-chloroiodobenzene (25.5 g, 80.9 mmol) was dissolved in dry THF (400 mL) and cooled to −60° C. Isopropylmagnesium chloride (2 M in THF, 40.4 mL, 80.9 mmol) was added under stirring during 30 minutes. The reaction mixture was allowed to warm up to −40° C. and the mixture was stirred at −40° C. for 4 h. Compound 491 (22.2 g, 80.9 mmol) was added and the mixture was stirred at −40° C. for 3 h after which it was allowed to warm to room temperature and stirred for 17 h. A saturated aqueous solution of NH4Cl (200 mL) was added and the mixture was stirred for 1 h. The phases were separated and the aqueous phase was extracted with Et2O (4×100 mL). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using CH2Cl2/petroleum ether (40-60) 2:3 as the eluent to afford the title compound as yellow crystalline compound. using dry glassware to warm up to −40° C. the mixture was stirred at −40° C. for 4 h the mixture was stirred at −40° C. for 3 h after which it to warm to room temperature stirred for 17 h the mixture was stirred for 1 h The phases were separated the aqueous phase was extracted with Et2O (4×100 mL) The combined organic phases were washed with brine dried (MgSO4) filtered concentrated in vacuo The crude product was purified by flash chromatography

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

Procedure: Using a procedure analogous to that used to prepare 30A, 4-bromo-2-chloro-1-iodobenzene (8 g, 25 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 160° C. for 1 h and worked up in a manner similar as in 30A to yield 61A (5.2 g, 96%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.41 (d, J=11.86 Hz, 1 H) 7.02 (dd, J=17.36, 11.21 Hz, 1 H) 7.35 (dd, 1 H) 7.41 (d, 1 H) 7.52 (d, J=1.76 Hz, 1 H).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 6-amino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (6) (8.00 g, 34.16 mmol) and cesium carbonate (22.48 g, 68.31 mmol) in anhydrous anisole (76 mL) under nitrogen was added 4-bromo-2-chloroiodobenzene (1.60 g, 1.10 equiv., 4.88 mmol). The preformed catalyst, as prepared above, was then added to the mixture to provide a dark brown suspension, which was heated at 100±2° C., with stirring at 350 rpm. The reaction was monitored by HPLC analysis. After 41 hours, no 6-amino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (6) remained. The reaction mixture was cooled to about 80° C. and 1M sulfuric acid (40.99 mL 40.99 mmol) was added. Gas evolution was observed after 10 minutes and the rate of addition was controlled to moderate the effervescence. At the end of the addition the pH was between 7 and 8. Additional sulfuric acid (1M, 10.25 mL, 10.25 mmol) was then added to give mobile slurry with a pH of 0. The mixture was diluted with anisole (20 mL) and Celatom FW-14 filter agent was added. It was then filtered at about 80° C. through a water-wet pad of Celatom FW-14 filter agent and the cake was washed with anisole (1×40 mL+3×20 mL), then water (10 mL). The lower aqueous layer was separated and discarded and the organic layer was washed with 10% aqueous NaCl solution (2×40 mL). This was added to a sodium hydroxide (5.46 g, 68.3 mmol) in methanol (24 mL) and the mixture was heated at 65° C. with stirring. After 17.5 hours HPLC analysis indicated that the hydrolysis of the ester was complete and the slurry was cooled to 15° C., then filtered on a sinter. The solid was washed with water (4×24 mL), MTBE (24 mL), and acetonitrile (2×25 mL) and then dried at 45° C. in a vacuum oven to provide 11.07 g of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (7) as a fine pale brown solid (assay 93.7% by 1H NMR), actual wt 10.37 g (72.2% yield). 1H NMR (400 MHz, d6 DMSO) δ 3.85 (3H, s, NMe), 6.53 (1H, dd, J 9, 7, Ar—H), 7.27 (1H, dd, J 9, 2.5, Ar—H), 7.56 (1H, d, J 9, Ar—H), 7.97 (1H, s, Ar—H), 8.20 (1H, s, Ar—H), 11.5 (1H, s, CO2H). 13C NMR (100 MHz, d6 DMSO) δ 31 (CH3), 108 (CH, d, J 2), 109 (CH), 117 (C, d, J 6), 122 (C), 124 (C, d, J 7), 127 (C), 130 (C), 131 (C), 132 (C, d, J 9), 133 (C, d, J 11), 141 (C), 145 (CF, d, J 252), 146 (CH), 170 (C═O). The preformed catalyst, as prepared above, was then added to the mixture to provide a dark brown suspension, which The reaction mixture was cooled to about 80° C. Gas evolution was observed after 10 minutes the rate of addition At the end of the addition the pH was between 7 and 8 to give mobile slurry with a pH of 0 filter agent was added It was then filtered at about 80° C. through a water-wet pad of Celatom FW-14 filter agent the cake was washed with anisole (1×40 mL+3×20 mL) The lower aqueous layer was separated the organic layer was washed with 10% aqueous NaCl solution (2×40 mL) the mixture was heated at 65° C. with stirring the slurry was cooled to 15° C. filtered on a sinter The solid was washed with water (4×24 mL), MTBE (24 mL), and acetonitrile (2×25 mL) dried at 45° C. in a vacuum oven

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 6-amino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (6) (8.00 g, 34.16 mmol) and cesium carbonate (22.48 g, 68.31 mmol) in anhydrous anisole (76 mL) under nitrogen was added 4-bromo-2-chloroiodobenzene (1.60 g, 1.10 equiv., 4.88 mmol). The preformed catalyst, as prepared above, was then added to the mixture to provide a dark brown suspension, which was heated at 100±2° C., with stirring at 350 rpm. The reaction was monitored by HPLC analysis. After 41 hours, no 6-amino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (6) remained. The reaction mixture was cooled to about 80° C. and 1M sulfuric acid (40.99 mL 40.99 mmol) was added. Gas evolution was observed after 10 minutes and the rate of addition was controlled to moderate the effervescence. At the end of the addition the pH was between 7 and 8. Additional sulfuric acid (1M, 10.25 mL, 10.25 mmol) was then added to give mobile slurry with a pH of 0. The mixture was diluted with anisole (20 mL) and Celatom FW-14 filter agent was added. It was then filtered at about 80° C. through a water-wet pad of Celatom FW-14 filter agent and the cake was washed with anisole (1×40 mL+3×20 mL), then water (10 mL). The lower aqueous layer was separated and discarded and the organic layer was washed with 10% aqueous NaCl solution (2×40 mL). This was added to a sodium hydroxide (5.46 g, 68.3 mmol) in methanol (24 mL) and the mixture was heated at 65° C. with stirring. After 17.5 hours HPLC analysis indicated that the hydrolysis of the ester was complete and the slurry was cooled to 15° C., then filtered on a sinter. The solid was washed with water (4×24 mL), MTBE (24 mL), and acetonitrile (2×25 mL) and then dried at 45° C. in a vacuum oven to provide 11.07 g of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (7) as a fine pale brown solid (assay 93.7% by 1H NMR), actual wt 10.37 g (72.2% yield). 1H NMR (400 MHz, d6 DMSO) δ 3.85 (3H, s, NMe), 6.53 (1H, dd, J 9, 7, Ar—H), 7.27 (1H, dd, J 9, 2.5, Ar—H), 7.56 (1H, d, J 9, Ar—H), 7.97 (1H, s, Ar—H), 8.20 (1H, s, Ar—H), 11.5 (1H, s, CO2H). 13C NMR (100 MHz, d6 DMSO) δ 31 (CH3), 108 (CH, d, J 2), 109 (CH), 117 (C, d, J 6), 122 (C), 124 (C, d, J 7), 127 (C), 130 (C), 131 (C), 132 (C, d, J 9), 133 (C, d, J 11), 141 (C), 145 (CF, d, J 252), 146 (CH), 170 (C═O). The preformed catalyst, as prepared above, was then added to the mixture to provide a dark brown suspension, which The reaction mixture was cooled to about 80° C. Gas evolution was observed after 10 minutes the rate of addition At the end of the addition the pH was between 7 and 8 to give mobile slurry with a pH of 0 filter agent was added It was then filtered at about 80° C. through a water-wet pad of Celatom FW-14 filter agent the cake was washed with anisole (1×40 mL+3×20 mL) The lower aqueous layer was separated the organic layer was washed with 10% aqueous NaCl solution (2×40 mL) the mixture was heated at 65° C. with stirring the slurry was cooled to 15° C. filtered on a sinter The solid was washed with water (4×24 mL), MTBE (24 mL), and acetonitrile (2×25 mL) dried at 45° C. in a vacuum oven

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

Procedure: 3-chloro-4-iodobromobenzene (3.1 g) was dissolved in diethyl ether (100 ml). To the solution was then added dropwise a hexane solution of n-butyl lithium (1.59 M, 6.1 ml) at −78° C. The mixture was then stirred at the same temperature for 30 minutes. To the mixture was then added dropwise trimethylsilyl trifluoromethane sulfonate (3.77 ml; 17.4 mmol). The mixture was then stirred for 1 hour. After the quenching of the reaction by gradually adding water over an ice bath, the product was then extracted with ether. The resulting organic phase was then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The crude product thus obtained was then purified twice through silica gel column chromatography (silica gel produced by Merck Ltd., Japan; hexane) to obtain 3-chloro-4-trimethylsilyl-bromobenzene (2.3 g) (yield: 90%). The mixture was then stirred for 1 hour After the quenching of the reaction by gradually adding water over an ice bath the product was then extracted with ether The resulting organic phase was then dried over magnesium sulfate The solvent was then distilled off under reduced pressure The crude product thus obtained was then purified twice through silica gel column chromatography (silica gel produced by Merck Ltd., Japan; hexane)

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

Procedure: 3-chloro-4-iodobromobenzene (3.1 g) was dissolved in diethyl ether (100 ml). To the solution was then added dropwise a hexane solution of n-butyl lithium (1.59 M, 6.1 ml) at −78° C. The mixture was then stirred at the same temperature for 30 minutes. To the mixture was then added dropwise trimethylsilyl trifluoromethane sulfonate (3.77 ml; 17.4 mmol). The mixture was then stirred for 1 hour. After the quenching of the reaction by gradually adding water over an ice bath, the product was then extracted with ether. The resulting organic phase was then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The crude product thus obtained was then purified twice through silica gel column chromatography (silica gel produced by Merck Ltd., Japan; hexane) to obtain 3-chloro-4-trimethylsilyl-bromobenzene (2.3 g) (yield: 90%). The mixture was then stirred for 1 hour After the quenching of the reaction by gradually adding water over an ice bath the product was then extracted with ether The resulting organic phase was then dried over magnesium sulfate The solvent was then distilled off under reduced pressure The crude product thus obtained was then purified twice through silica gel column chromatography (silica gel produced by Merck Ltd., Japan; hexane)