2-tert-butyl-4-chloroaniline

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-tert-butyl-4-chloroaniline (Reference Example 19, 16.7 g, 90.8 mmol) and bis(2-chloroethyl)amine hydrochloride (17.8 g, 99.9 mmol) in diglyme (170 mL) was stirred at 170° C. for 3 days under nitrogen atmosphere. After this time, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 M NaOH. The organic layer was washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash column chromatography (NH-silica gel, 1:1-0:100 hexane/ethyl acetate, 10:1 ethyl acetate/MeOH) to provide an impure brown oil and a brown solid. The solid was dissolved in ethyl acetate and the solution was treated with 4 M HCl in ethyl acetate to give the title compound (2.17 g) as a brown solid. The impure brown oil was partitioned between ethyl acetate and 1 M HCl and the resulting white precipitate was collected by filtration, and washed with diethyl ether to give the title compound (2.98 g) as a white solid. After this time, the reaction mixture was cooled to room temperature partitioned between ethyl acetate and 1 M NaOH The organic layer was washed with water, and saturated brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The resulting brown oil was purified by flash column chromatography (NH-silica gel, 1:1-0:100 hexane/ethyl acetate, 10:1 ethyl acetate/MeOH) to provide an impure brown oil

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-tert-butyl-4-chloroaniline (Reference Example 19, 16.7 g, 90.8 mmol) and bis(2-chloroethyl)amine hydrochloride (17.8 g, 99.9 mmol) in diglyme (170 mL) was stirred at 170° C. for 3 days under nitrogen atmosphere. After this time, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 M NaOH. The organic layer was washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash column chromatography (NH-silica gel, 1:1-0:100 hexane/ethyl acetate, 10:1 ethyl acetate/MeOH) to provide an impure brown oil and a brown solid. The solid was dissolved in ethyl acetate and the solution was treated with 4 M HCl in ethyl acetate to give the title compound (2.17 g) as a brown solid. The impure brown oil was partitioned between ethyl acetate and 1 M HCl and the resulting white precipitate was collected by filtration, and washed with diethyl ether to give the title compound (2.98 g) as a white solid. After this time, the reaction mixture was cooled to room temperature partitioned between ethyl acetate and 1 M NaOH The organic layer was washed with water, and saturated brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The resulting brown oil was purified by flash column chromatography (NH-silica gel, 1:1-0:100 hexane/ethyl acetate, 10:1 ethyl acetate/MeOH) to provide an impure brown oil

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(2-tert-butyl-4-chlorophenyl)acetamide (Reference Example 18, 4.78 g, 21.2 mmol), concentrated HCl (50 mL) and EtOH (10 mL) was stirred at 110° C. for 5 h. After cooling, the reaction mixture was basified with 8 M NaOH under ice-cooling. The mixture was extracted with ethyl acetate and the organic layer was washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.29 g) as a colorless oil. After cooling cooling The mixture was extracted with ethyl acetate the organic layer was washed with water, and saturated brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-tert-butyl-4-chloroaniline (Reference Example 19, 16.7 g, 90.8 mmol) and bis(2-chloroethyl)amine hydrochloride (17.8 g, 99.9 mmol) in diglyme (170 mL) was stirred at 170° C. for 3 days under nitrogen atmosphere. After this time, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 M NaOH. The organic layer was washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash column chromatography (NH-silica gel, 1:1-0:100 hexane/ethyl acetate, 10:1 ethyl acetate/MeOH) to provide an impure brown oil and a brown solid. The solid was dissolved in ethyl acetate and the solution was treated with 4 M HCl in ethyl acetate to give the title compound (2.17 g) as a brown solid. The impure brown oil was partitioned between ethyl acetate and 1 M HCl and the resulting white precipitate was collected by filtration, and washed with diethyl ether to give the title compound (2.98 g) as a white solid. After this time, the reaction mixture was cooled to room temperature partitioned between ethyl acetate and 1 M NaOH The organic layer was washed with water, and saturated brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The resulting brown oil was purified by flash column chromatography (NH-silica gel, 1:1-0:100 hexane/ethyl acetate, 10:1 ethyl acetate/MeOH) to provide an impure brown oil

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(2-tert-butyl-4-chlorophenyl)acetamide (Reference Example 18, 4.78 g, 21.2 mmol), concentrated HCl (50 mL) and EtOH (10 mL) was stirred at 110° C. for 5 h. After cooling, the reaction mixture was basified with 8 M NaOH under ice-cooling. The mixture was extracted with ethyl acetate and the organic layer was washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.29 g) as a colorless oil. After cooling cooling The mixture was extracted with ethyl acetate the organic layer was washed with water, and saturated brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure