Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 1 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 4 h; Inert atmosphere
[0137] A solution of 4-aminophenol (256 mg, 2.35 mmol) in dry N,Ndimethylformamide (40 mL) was treated with potassium tert-butoxide (274 mg, 2.44 mmol), and the reddish-brown mixture was stirred at room temperature for 1 hour. The contents were treated with 3a and 3b (400 mg, 2.35 mmol) and potassium carbonate (974 mg, 7.05 mmol) and then heated to 80 °C under argon for 4 h. The mixture was cooled to room temperature and poured into ethyl acetate (100 mL) and brine (400 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated. The crude reaction mixture was purified by column chromatography (dichloromethane/methanol) to afford the desired 4-(4-aminophenoxy)-N- methylpyridine-2-carboxamide 4a (400 mg, 1 .65 mmol, 70percent) and 4-(4- aminophenoxy)-N,N-dimethylpyridine-2-carboxamide (69percent) 4b after column as a light-brown solid.
With triethylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃;
Step 1.Synthesis of 4-Chloro-pyridine-2-carboxylic acid dimethylamide: A solution of 4-chloro-pyridine-2-carbonyl chloride (1 eq) in dichloromethane was cooled to 0 C., whereupon triethylamine (2 eq) was added followed by dimethylamine (2 eq, 2M solution in THF).The solution was allowed to warm to room temperature and let stir overnight.It was then washed with 1M NaOH. The separated organic layer is dried over MgSO4, filtered, and concentrated to yield the desired product. HPLC, 1.82 min; MS: MH+=185.6
Step 2.Synthesis of 4-(4-Amino-3-nitro-phenoxy)-pyridine-2-carboxylic acid dimethylamide: A mixture containing 4-amino-3-nitrophenol (1 eq) and potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature.To this mixture was added <strong>[114780-06-2]4-Chloro-pyridine-2-carboxylic acid dimethylamide</strong> (1 eq) and potassium carbonate (1.2 eq) and then it was stirred at 90 C. for 3 days.The reaction mixture was then concentrated before partitioning between ethyl acetate and water.The organic layer was separated, washed with brine, dried, filtered and concentrated in vacuum to give brown solid.Purification by flash chromatography with ethyl acetate and hexane (1:1) gave the desired product as a yellow syrup. HPLC, 1.69 min; MS: MH+=303.1.
4-chloro-2-pyridine carboxylic acid chloride hydrochloride[ No CAS ]
[ 124-40-3 ]
[ 114780-06-2 ]
Yield
Reaction Conditions
Operation in experiment
94%
In tetrahydrofuran; at 0 - 20℃; for 5h;Inert atmosphere;
[0136] The acid chloride 2 (500 mg, 2.87 mmol) was added portion wise to dimethylamine (2.0 M) in tetrahydrofuran (100 mL) at 0 00 under argon. The mixture was stirred at 0 00 for 1 hour then at room temperature for 4 hours, concentrated to near dryness, and dissolved in ethyl acetate (50 mL). The organics were washed with brine, dried over sodium sulfate, and concentrated. The crude reaction mixture was purified by column chromatography (dichloromethane/methanol) to provide the 4-chloro-N,N- dimethylpyridine-2-carboxamide 3b (459 mg, 2.7 mmol, 94%) as a yellow, crystalline solid. 1H NMR (DMSO-d6, 400 MHz): d 2.83 (5, 6H); 7.71 (dd, J = 2.2, 5.1 Hz, 1H); 8.02 (d, J = 2.2, 1H); 8.65 (d, J = 5.1 Hz, 1H); MS (APOI+, Mi-i) 184.68.
[0137] A solution of 4-aminophenol (256 mg, 2.35 mmol) in dry N,Ndimethylformamide (40 mL) was treated with potassium tert-butoxide (274 mg, 2.44 mmol), and the reddish-brown mixture was stirred at room temperature for 1 hour. The contents were treated with 3a and 3b (400 mg, 2.35 mmol) and potassium carbonate (974 mg, 7.05 mmol) and then heated to 80 C under argon for 4 h. The mixture was cooled to room temperature and poured into ethyl acetate (100 mL) and brine (400 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated. The crude reaction mixture was purified by column chromatography (dichloromethane/methanol) to afford the desired 4-(4-aminophenoxy)-N- methylpyridine-2-carboxamide 4a (400 mg, 1 .65 mmol, 70%) and 4-(4- aminophenoxy)-N,N-dimethylpyridine-2-carboxamide (69%) 4b after column as a light-brown solid.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
88K+ Compounds
Competitive Price
1-2 Day Shipping
