2-bromo-4-(bromomethyl)-1-chlorobenzene

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

Procedure: Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-bromo-4-bromomethyl-1-chloro-benzene, to give the title compound. similar to the Preparation 177

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, 140.2 ml (1.0 mol) of diisopropylamine were dissolved in 1200 ml of dry THF and cooled to −30° C. 400 ml (1.0 mol) of n-butyllithium solution (2.5 M in hexane) were added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 94.8 g (0.667 mol) of tert-butyl cyclopropanecarboxylate in 750 ml THF was added to the reaction solution, with the temperature being kept below −60° C. After 4 h of stirring at −60° C., a solution of 208.6 g (0.733 mol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 550 ml of THF was added, the temperature again being kept below −60° C. The reaction mixture was slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added carefully. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 4:1). This gave 95.5 g (41.4% of theory) of the title compound. The resulting mixture was warmed to 0° C. cooled to −70° C being kept below −60° C again being kept below −60° C The reaction mixture was slowly warmed to RT overnight After phase separation the aqueous phase was extracted with ethyl acetate The combined organic phases were dried over magnesium sulphate concentrated under reduced pressure The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 4:1)

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 260 g (about 1.05 mol) of crude (3-bromo-4-chlorophenyl)methanol were dissolved in 2.86 liters of dichloromethane, the solution was cooled to −5° C. and 127.1 g (44.6 ml, 460 mmol) of phosphorus tribromide were added slowly. After the end of the addition, the mixture was stirred at −5° C. for another 1 h and then diluted with diluted with dichloromethane and water. The organic phase was removed, dried over magnesium sulphate and concentrated under reduced pressure. This gave, as a crude product, 280.5 g (about 84% of theory) of 2-bromo-4-(bromomethyl)-1-chlorobenzene. After the end of the addition diluted The organic phase was removed dried over magnesium sulphate concentrated under reduced pressure

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 260 g (about 1.05 mol) of crude (3-bromo-4-chlorophenyl)methanol were dissolved in 2.86 liters of dichloromethane, the solution was cooled to −5° C. and 127.1 g (44.6 ml, 460 mmol) of phosphorus tribromide were added slowly. After the end of the addition, the mixture was stirred at −5° C. for another 1 h and then diluted with diluted with dichloromethane and water. The organic phase was removed, dried over magnesium sulphate and concentrated under reduced pressure. This gave, as a crude product, 280.5 g (about 84% of theory) of 2-bromo-4-(bromomethyl)-1-chlorobenzene. After the end of the addition diluted The organic phase was removed dried over magnesium sulphate concentrated under reduced pressure

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

Procedure: Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-bromo-4-bromomethyl-1-chloro-benzene, to give the title compound. similar to the Preparation 177

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, 4.0 ml (28.8 mmol) of diisopropylamine were dissolved in 50 ml of dry THF, and the mixture was cooled to −30° C. 11.5 ml (28.8 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 2.77 g (19.2 mmol) of tert-butyl-2-methylpropanoate in 20 ml of THF was then added, the temperature being kept below −60° C. After 4 h of stirring at −60° C., a solution of 6.0 g (21.1 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 30 ml of THF was added, the reaction temperature once more being kept below −60° C. The reaction mixture was stirred overnight slowly warming to RT, and saturated aqueous ammonium chloride solution and ethyl acetate were then added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1). This gave 5.6 g (84% of theory) of the title compound. The resulting mixture was warmed to 0° C. cooled to −70° C being kept below −60° C once more being kept below −60° C The reaction mixture was stirred overnight slowly warming to RT After phase separation the aqueous phase was extracted twice with ethyl acetate The combined organic phases were dried over magnesium sulphate concentrated under reduced pressure The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, 2.9 ml (20.8 mmol) of diisopropylamine were dissolved in 30 ml of dry THF, and the mixture was cooled to −20° C. 8.3 ml (20.8 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise, and the resulting mixture was stirred to −20° C. for 30 min and then cooled to −78° C. At this temperature, a solution of 2.60 g (about 15.3 mmol, crude) of tert-butyl cyclobutylacetate in 10 ml of THF was added. After 4 h of stirring at −78° C., a solution of 3.95 g (13.9 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 10 ml of THF was added. The reaction mixture was slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The solid that remained was triturated with 30 ml of cyclohexane/dichloromethane (1:1) and filtered off. The solid was once more triturated with 10 ml of cyclohexane/dichloromethane (1:1) and again filtered off; this procedure was repeated once more. All filtrates were collected, combined and concentrated under reduced pressure. This residue was then purified further by chromatography on silica gel (mobile phase from pure cyclohexane to cyclohexane/dichloromethane 20:1 to 10:1). This gave 2.24 g of the title compound (43.2% of theory). cooled to −78° C After 4 h of stirring at −78° C. The reaction mixture was slowly warmed to RT overnight The mixture was extracted three times with ethyl acetate The combined organic phases were dried over magnesium sulphate concentrated under reduced pressure The solid that remained was triturated with 30 ml of cyclohexane/dichloromethane (1:1) filtered off The solid was once more triturated with 10 ml of cyclohexane/dichloromethane (1:1) again filtered off All filtrates were collected concentrated under reduced pressure This residue was then purified further by chromatography on silica gel (mobile phase from pure cyclohexane to cyclohexane/dichloromethane 20:1 to 10:1)

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, 5.8 ml (41.6 mmol) of diisopropylamine were dissolved in 50 ml of dry THF, and the mixture was cooled to −30° C. 16.6 ml (41.6 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise, and the resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 5.06 g (32.0 mmol) of tert-butyl 2-methylbutanoate in 20 ml of THF was added, the reaction temperature being kept below −60° C. After 4 h of stirring at −60° C., a solution of 10.0 g (35.2 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 30 ml of THF was added, and the temperature was once more kept below −60° C. The reaction mixture was then slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution and ethyl acetate were then added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1). This gave 7.62 g (65.9% of theory) of the title compound. the resulting mixture was warmed to 0° C. cooled to −70° C being kept below −60° C was once more kept below −60° C The reaction mixture was then slowly warmed to RT overnight After phase separation the aqueous phase was extracted twice with ethyl acetate The combined organic phases were dried over magnesium sulphate concentrated under reduced pressure The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1)

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 260 g (about 1.05 mol) of crude (3-bromo-4-chlorophenyl)methanol were dissolved in 2.86 liters of dichloromethane, the mixture was cooled to −5° C. and 127.1 g (44.6 ml, 460 mmol) of phosphorous tribromide were added slowly. After the addition had ended, stirring at −5° C. was continued for 1 h, and the mixture was then diluted with dichloromethane and water. The organic phase was separated off, dried over magnesium sulphate and concentrated under reduced pressure. This gave, as a crude product, 280.5 g (about 84% of theory) of 2-bromo-4-(bromomethyl)-1-chlorobenzene. After the addition The organic phase was separated off dried over magnesium sulphate concentrated under reduced pressure

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, 140.2 ml (1.0 mol) of diisopropylamine were dissolved in 1200 ml of dry THF, and the mixture was cooled to −30° C. 400 ml (1.0 mol) of n-butyllithium solution (2.5 M in hexane) were added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 94.8 g (0.667 mol) of tert-butyl cyclopropanecarboxylate in 750 ml of THF was added to the reaction solution, and during the addition the temperature was kept below −60° C. After 4 h of stirring at −60° C., a solution of 208.6 g (0.733 mol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 550 ml of THF was added, and once more the temperature was kept below −60° C. during the addition. The reaction mixture was slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added carefully. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 4:1). This gave 95.5 g (41.4% of theory) of the title compound. The resulting mixture was warmed to 0° C. cooled to −70° C during the addition the temperature was kept below −60° C once more the temperature was kept below −60° C. during the addition The reaction mixture was slowly warmed to RT overnight After phase separation the aqueous phase was extracted with ethyl acetate The combined organic phases were dried over magnesium sulphate concentrated under reduced pressure The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 4:1)

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 260 g (crude product of several batches, about 1.05 mol) of (3-bromo-4-chlorophenyl)methanol were dissolved in 2.86 liters of dichloromethane, the mixture was cooled to −5° C. and 127.1 g (44.6 ml, 459.6 mmol) of phosphorus tribromide were added slowly. After the addition had ended, the mixture was stirred at −5° C. for another 1 h and then diluted with dichloromethane and water. The organic phase was separated off, dried over magnesium sulphate and concentrated under reduced pressure. This gave, as a crude product, 280.5 g (about 84% of theory) of 2-bromo-4-(bromomethyl)-1-chlorobenzene. After the addition The organic phase was separated off dried over magnesium sulphate concentrated under reduced pressure

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

Procedure: Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-bromo-4-bromomethyl-1-chloro-benzene, to give the title compound. similar to the Preparation 177