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With sodium hydroxide; In DMF (N,N-dimethyl-formamide); at 0 - 70℃; for 16.25h;
4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485 mmol) in N, N-dimethylformamide (150 mL) and the suspension was maintained for 15 min at rt. The reaction mixture was cooled to 0 C and was treated with <strong>[383-62-0]ethyl chlorodifluoroacetate</strong> (329 mmol). The reaction mixture was heated at 70 C for 16 h and was concentrated. The residue was diluted with ice water (200 mL) and was extracted with ethyl acetate (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the difluoromethyl ether in 59% yield as a yellow oil.
59%
Procedure 6 Procedure 6 provides a method for the preparation of 6-difluoromethoxyindazole-3-acid from 4-nitrophenol. 4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485 mmol) in N,N-dimethylformamide (150 mL) and the suspension was maintained for 15 min at rt. The reaction mixture was cooled to 0 C. and was treated with <strong>[383-62-0]ethyl chlorodifluoroacetate</strong> (329 mmol). The reaction mixture was heated at 70 C. for 16 h and was concentrated. The residue was diluted with ice water (200 mL) and was extracted with ethyl acetate (3*100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the difluoromethyl ether in 59% yield as a yellow oil.
4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485 mmol) in NN-dimethylformamide (150 mL) and the suspension was maintained for 15 min at rt. The reaction mixture was cooled to 0 C and was treated with <strong>[383-62-0]ethyl chlorodifluoroacetate</strong> (329 mmol). The reaction mixture was heated at 70 C for 16 h and was concentrated. The residue was diluted with ice water (200 mL) and was extracted with ethyl acetate (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the difluoromethyl ether in 59% yield as yellow oil. The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3x100mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid. Acetic anhydride (19.6 mmol) was added to a solution of the acetamide (13.2 mmol) in chloroform (20 mL) and the reaction mixture was warmed to reflux. Fuming nitric acid (16.0 mmol) was added dropwise and the reaction mixture was maintained at reflux for 30 min: The cooled solution was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3xlOmL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the nitro-amide in 83% yield. The amide (11.0 mmol), sodium hydroxide (43.8 mmol), and water (10 mL) were combined and the reaction mixture was maintained for 1.5 hour at 60 C. the reaction was allowed to cool to rt and the precipitated solids were isolated by filtration, and washed with water, and dried to provide the aniline in 98% yield as a light yellow solid. The aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and water (10 mL) and the reaction mixture was warmed to 80-90 C in order to completely dissolve the aniline. The reaction mixture. was cooled to 0 C and a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) was added during a 15 min period. The solution was maintained for 40 minutes at 0-5 C and filtered. Copper (I) bromide (18.8 mmol) was dissolved in 40% hydrobromic acid (21 mL) and was cooled to 0 C. The solution of the diazo salt was added slowly to the copper solution and the mixture was maintained for 30 min at 0-10 C. The reaction mixture was heated at 60 C for 30 min and then at 100 C for 10 min to ensure completion. The reaction mixture was allowed to cool to rt and was extracted with dichloromethane (3x40mL). The combined organic layers were washed with 1 M sodium hydroxide, water, 1 N hydrochloric acid, and water. The organic layer was dried (magnesium sulfate) and concentrated to provide the nitro bromide in 76% yield as a light yellow solid. Diethyl malonate (25.7 mmol) was added dropwise to a suspension of sodium hydride (25.8 mmol) in dimethylsulfoxide (5 mL) at 0 C. The reaction mixture was warmed to 60 C and maintained for 30 min. A solution of the nitro bromide (11.7 mmol) in dimethylsulfoxide (7 mL) was added dropwise and the reaction mixture was heated at 100 C for 5 h. The cooled solution was poured onto ice water and the aqueous layer was extracted with dichloromethane (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester as an oil. The diester (11.7 mmol), sodium hydroxide (35 mmol), and water (20 mL) were combined and heated at 60 C for 1 h. The reaction mixture was allowed to cool to rt and the aqueous layer was washed with dichloromethane (3x100 mL). The pH of the aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60 C for 1 h. The suspension was cooled to 0 C and the solids were collected by filtration and dried to provide the acid in 64% yield. Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0 C. After 30 min, the acid (7.69 mmol) was added and the reaction mixture was heated at reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (2x20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the ester in 94% yield ...
59%
Procedure 8 provides a method for the preparation of 6-difluoromethoxyindazole-3-acid from 4-nitrophenol. 4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485 mmol) in N,N-dimethylformamide (150 mL) and the suspension was maintained for 15 min at rt. The reaction mixture was cooled to 0 C. and was treated with <strong>[383-62-0]ethyl chlorodifluoroacetate</strong> (329 mmol). The reaction mixture was heated at 70 C. for 16 h and was concentrated. The residue was diluted with ice water (200 mL) and was extracted with ethyl acetate (3*100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the difluoromethyl ether in 59% yield as a yellow oil.
59%
4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485 mmol) in N,N-dimethylformamide (150 mL) and the suspension was maintained for 15 min at rt. The reaction mixture was cooled to 0 0C and was treated with <strong>[383-62-0]ethyl chlorodifluoroacetate</strong> (329 mmol). The reaction mixture was heated at 70 0C for 16 h and was concentrated. The residue was diluted with ice water (200 mL) and was extracted with ethyl acetate (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the difluoromethyl ether in 59% yield as a yellow oil.
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