4-iodo-2-(trifluoromethoxy)aniline

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (200 mg, 344 μmol, Eq: 1.00), was combined with CH2Cl2 (5 ml) to give a clear solution. DIPEA (178 mg, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 30 minutes. 4-Iodo-2-(trifluoromethoxy) aniline (136 mg, 447 μmol, Eq: 1.3) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc/Hexanes) to give the desired product as a white solid. 255 mg. (ES+) m/z Calcd: [(M+)+]: 752. found: 752. to give a clear solution the reaction mixture was stirred at RT overnight The crude reaction mixture was concentrated in vacuum The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc/Hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) and acidified with HCl in methanol to afford the desired product as its hydrochloride salt (0.573 g, 98% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)