2-chloro-4-fluoro-5-hydrazinylphenol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-2-fluoro-5-hydroxyaniline (32.5 g) was added to conc. hydrochloric acid (300 ml), and a solution of sodium nitrite (15.2 g) in water (20 ml) was added thereto at 0° to -5° C. The resultant mixture was stirred at 0° to 5° C. for 30 minutes, and urea was added thereto to rremove excessive nitrite ion, followed by cooling to -30° C. A solution of stannous chloride (92 g) in hydrochloric acid (160 ml) was added thereto, and the mixture was stirred at 0° to -10° C. for 3 hours. The reaction mixture was filtered, and the precipitated crystals were dissolved in water, neutralized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was treated with ether to give 4-chloro-2-fluoro-5-hydroxyphenylhydrazine (8.4 g) as crystals. The crystals were added to a solution of 2 -hydroxyiminocyclohexanone morpholinoenamine (9.35 g), ethanol (90 ml) and a catalytic amount of acetic acid and heated under reflux for 3 hours. After cooling, ethanol was removed by evaporation, and water was added to the residue, followed by extraction with ethyl acetate. The extract was dried and concentrated, and the residue was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to give 2-(4-chloro-2-fluoro-5-hydroxyphenyl)hydrazonocyclohexanone oxime (8 g) as crystals. The crystals were suspended in a mixture of tetrahydrofuran (50 ml) and 15% pyridine-water (112 ml). A solution of cupric sulfate (CuSO4.5H2O) (11.2 g) in water (40 ml) was added to the suspension, which was heated under reflux for an additional 2 hours. After cooling, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with an aqueous solution of cupric sulfate, dried and concentrated. The residue was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to give 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (4 g) as crystals. M.P., 220°-221° C. (decomp.). at 0° to -5° C The reaction mixture was filtered the precipitated crystals were dissolved in water extracted with ethyl acetate The organic layer was washed with water dried concentrated The residue was treated with ether

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-2-fluoro-5-hydroxyaniline (32.5 g) was added to conc. hydrochloric acid (300 ml), and a solution of sodium nitrite (15.2 g) in water (20 ml) was added thereto at 0° to -5° C. The resultant mixture was stirred at 0° to 5° C. for 30 minutes, and urea was added thereto to rremove excessive nitrite ion, followed by cooling to -30° C. A solution of stannous chloride (92 g) in hydrochloric acid (160 ml) was added thereto, and the mixture was stirred at 0° to -10° C. for 3 hours. The reaction mixture was filtered, and the precipitated crystals were dissolved in water, neutralized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was treated with ether to give 4-chloro-2-fluoro-5-hydroxyphenylhydrazine (8.4 g) as crystals. The crystals were added to a solution of 2 -hydroxyiminocyclohexanone morpholinoenamine (9.35 g), ethanol (90 ml) and a catalytic amount of acetic acid and heated under reflux for 3 hours. After cooling, ethanol was removed by evaporation, and water was added to the residue, followed by extraction with ethyl acetate. The extract was dried and concentrated, and the residue was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to give 2-(4-chloro-2-fluoro-5-hydroxyphenyl)hydrazonocyclohexanone oxime (8 g) as crystals. The crystals were suspended in a mixture of tetrahydrofuran (50 ml) and 15% pyridine-water (112 ml). A solution of cupric sulfate (CuSO4.5H2O) (11.2 g) in water (40 ml) was added to the suspension, which was heated under reflux for an additional 2 hours. After cooling, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with an aqueous solution of cupric sulfate, dried and concentrated. The residue was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to give 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (4 g) as crystals. M.P., 220°-221° C. (decomp.). at 0° to -5° C The reaction mixture was filtered the precipitated crystals were dissolved in water extracted with ethyl acetate The organic layer was washed with water dried concentrated The residue was treated with ether

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-2-fluoro-5-hydroxyaniline (10 g) was dissolved in conc. hydrochloric acid (130 ml) under heating, and the resultant mixture was cooled to 0° C. To the resulting mixture, there was dropwise added a solution of sodium nitrite (4.5 g) in water (20 ml). After completion of the addition, the mixture was further stirred at 5 to -5° C. for 1 hour, and urea was added thereto, whereby excessive sodium nitrite ion was decomposed. The resulting mixture was cooled to -30° to -25° C., and a solution of anhydrous stannous chloride (20.5 g) in conc. hydrochloric acid (40 ml) was added thereto, followed by stirring at -10° to 0° C. for 3 hours. The precipitated crystals were collected by filtration, washed with a small amount of water and dissolved in a 10% aqueous sodium hydroxide solution. The resultant solution was adjusted to pH 7 and extracted with ethyl acetate. The extract was dried and concentrated. The crystallized residue was washed with ether to obtain 1 g of 4-chloro-2-fluoro-5-hydroxyphenylhydrazine. m.p., 149°-150° C. (decomp.). under heating After completion of the addition The resulting mixture was cooled to -30° to -25° C. by stirring at -10° to 0° C. for 3 hours The precipitated crystals were collected by filtration washed with a small amount of water dissolved in a 10% aqueous sodium hydroxide solution extracted with ethyl acetate The extract was dried concentrated The crystallized residue was washed with ether

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

実験手順: 4-Chloro-2-fluoro-5-hydroxyphenylhydrazine (0.5 g), 2-acetylcyclohexanone (0.4 g) and a catalytic amount of acetic acid were admixed with xylene (15 ml), and the resultant mixture was heated under reflux for 5 hours while removing water. After cooling, the mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain 0.7 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole. m.p., 188.5°-190° C. under reflux for 5 hours while removing water After cooling the mixture was concentrated the residue was purified by silica gel column chromatography

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

実験手順: A solution of 2-fluoro-4-chloro-5-hydroxyphenylhydrazine (8 g) and 2-ethoxycarbonylcyclohexanone (8 g) in acetic acid (30 ml) was heated under reflux for 4 hours. After cooling, the precipitated crystals were collected by filtration and washed with ether to give 11 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,3a,4,5,6,7-hexahydroindazol-3-one. m.p., 273°-275° C. (decomp.). under reflux for 4 hours After cooling the precipitated crystals were collected by filtration washed with ether

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

実験手順: A solution of 2-fluoro-4-chloro-5-hydroxyphenylhydrazine (8 g) and 2-ethoxycarbonylcyclohexanone (8 g) in acetic acid (30 ml) was heated under reflux for 4 hours. After cooling, the precipitated crystals were collected by filtration and washed with ether to give 11 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,3a,4,5,6,7-hexahydroindazol-3-one. m.p., 273°-275° C. (decomp.). under reflux for 4 hours After cooling the precipitated crystals were collected by filtration washed with ether

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-2-fluoro-5-hydroxyaniline (32.5 g) was added to conc. hydrochloric acid (300 ml), and a solution of sodium nitrite (15.2 g) in water (20 ml) was added thereto at 0° to -5° C. The resultant mixture was stirred at 0 to 5° C. for 30 minutes, and urea was added thereto to remove excessive nitrite ion, followed by cooling to -30° C. A solution of stannous chloride (92 g) in hydrochloric acid (160 ml) was added thereto, and the mixture was stirred at 0° to -10° C. for 3 hours. The reaction mixture was filtered, and the precipitated crystals were dissolved in water, neutralized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was treated with ether to give 4-chloro-2-fluoro-5-hydroxyphenylhydrazine (8.4 g) as crystals. The crystals were added to a solution of 2-hydroxyiminocyclohexanone morpholinoenamine (9.35 g), ethanol (90 ml) and a catalytic amount of acetic acid and heated under reflux for 3 hours. After cooling, ethanol was removed by evaporation, and water was added to the residue, followed by extraction with ethyl acetate. The extract was dried and concentrated, and the residue was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to give 2-(4-chloro-2-fluoro-5-hydroxyphenyl)hydrazonocyclohexanone oxime (8 g) as crystals. The crystals were suspended in a mixture of tetrahydrofuran (50 ml) and 15% pyridine-water (112 ml). A solution of cupric sulfate (CuSO4.5H2O) (11.2 g) in water (40 ml) was added to the suspension, which was heated under reflux for an additional 2 hours. After cooling, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with an aqueous solution of cupric sulfate, dried and concentrated. The residue was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to give 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (4 g) as crystals. M.P., 220°-221° C. (decomp.). at 0° to -5° C to remove excessive nitrite ion A solution of stannous chloride (92 g) in hydrochloric acid (160 ml) was added The reaction mixture was filtered the precipitated crystals were dissolved in water extracted with ethyl acetate The organic layer was washed with water dried concentrated The residue was treated with ether

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-2-fluoro-5-hydroxyaniline (32.5 g) was added to conc. hydrochloric acid (300 ml), and a solution of sodium nitrite (15.2 g) in water (20 ml) was added thereto at 0° to -5° C. The resultant mixture was stirred at 0 to 5° C. for 30 minutes, and urea was added thereto to remove excessive nitrite ion, followed by cooling to -30° C. A solution of stannous chloride (92 g) in hydrochloric acid (160 ml) was added thereto, and the mixture was stirred at 0° to -10° C. for 3 hours. The reaction mixture was filtered, and the precipitated crystals were dissolved in water, neutralized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was treated with ether to give 4-chloro-2-fluoro-5-hydroxyphenylhydrazine (8.4 g) as crystals. The crystals were added to a solution of 2-hydroxyiminocyclohexanone morpholinoenamine (9.35 g), ethanol (90 ml) and a catalytic amount of acetic acid and heated under reflux for 3 hours. After cooling, ethanol was removed by evaporation, and water was added to the residue, followed by extraction with ethyl acetate. The extract was dried and concentrated, and the residue was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to give 2-(4-chloro-2-fluoro-5-hydroxyphenyl)hydrazonocyclohexanone oxime (8 g) as crystals. The crystals were suspended in a mixture of tetrahydrofuran (50 ml) and 15% pyridine-water (112 ml). A solution of cupric sulfate (CuSO4.5H2O) (11.2 g) in water (40 ml) was added to the suspension, which was heated under reflux for an additional 2 hours. After cooling, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with an aqueous solution of cupric sulfate, dried and concentrated. The residue was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as an eluent to give 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (4 g) as crystals. M.P., 220°-221° C. (decomp.). at 0° to -5° C to remove excessive nitrite ion A solution of stannous chloride (92 g) in hydrochloric acid (160 ml) was added The reaction mixture was filtered the precipitated crystals were dissolved in water extracted with ethyl acetate The organic layer was washed with water dried concentrated The residue was treated with ether

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: 4-Chloro-2-fluoro-5-hydroxyaniline (10 g) was dissolved in conc. hydrochloric acid (130 ml) under heating, and the resultant mixture was cooled to 0° C. To the resulting mixture, there was dropwise added a solution of sodium nitrite (4.5 g) in water (20 ml). After completion of the addition, the mixture was further stirred at 5° to -5° C. for 1 hour, and urea was added thereto, whereby excessive sodium nitrite ion was decomposed. The resulting mixture was cooled to -30° to -25° C., and a solution of anhydrous stannous chloride (20.5 g) in conc. hydrochloric acid (40 ml) was added thereto, followed by stirring at -10° to 0° C. for 3 hours. The precipitated crystals were collected by filtration, washed with a small amount of water and dissolved in a 10% aqueous sodium hydroxide solution. The resultant solution was adjusted to pH 7 and extracted with ethyl acetate. The extract was dried and concentrated. The crystallized residue was washed with ether to obtain 1 g of 4-chloro-2-fluoro-5-hydroxyphenylhydrazine. m.p. 149°-150° C. (decomp.). under heating After completion of the addition The resulting mixture was cooled to -30° to -25° C. by stirring at -10° to 0° C. for 3 hours The precipitated crystals were collected by filtration washed with a small amount of water dissolved in a 10% aqueous sodium hydroxide solution extracted with ethyl acetate The extract was dried concentrated The crystallized residue was washed with ether

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

実験手順: 4-Chloro-2-fluoro-5-hydroxyphenylhydrazine (0.5 g), 2-acetylcyclohexanone (0.4 g) and a catalytic amount of acetic acid were admixed with xylene (15 ml), and the resultant mixture was heated under reflux for 5 hours while removing water. After cooling, the mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain 0.7 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole. m.p., 188.5°-190° C. under reflux for 5 hours while removing water After cooling the mixture was concentrated the residue was purified by silica gel column chromatography