2-fluoro-6-methoxyaniline

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

Procedure: (2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methoxy-phenyl)-amine was prepared from 2,4,5-Trichloro-pyrimidine and 2-Fluoro-6-methoxyaniline in an analogous manner to Example 1230a. Title product was obtained as an off white solid (3.80 g, 62%). MP=133-135. LCMS 289.03 (M+H), HPLC purity=94%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.24 (s, 1H), 8.35 (s, 1H), 7.39-7.35 (m, 1H), 7.00-6.91 (m, 2H), 3.80 (s, 3H).

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

Procedure: 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethyl-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a solution of triphosgene (92 mg) in dichloromethane was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 3-fluoro-o-anisidine (44 μl) was added to the reaction solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 126 mg (yield 83%) of the title compound. the mixture was stirred at room temperature overnight the mixture was extracted with chloroform The chloroform layer was dried over sodium sulfate The solvent was removed by distillation under the reduced pressure The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1)

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

Procedure: 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a solution of triphosgene (110 mg) in dichloromethane was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 3-fluoro-o-anisidine (132 μl) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hr. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (91/9) to give 23 mg (yield 13%) of the title compound. the mixture was stirred at room temperature for 2 hr the solvent was removed by distillation under the reduced pressure The residue was purified by chromatography on silica gel by development with chloroform/methanol (91/9)

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

Procedure: 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (120 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a solution of triphosgene (110 mg) in dichloromethane was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 3-fluoro-o-anisidine (132 μl) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hr. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (91/9) to give 23 mg (yield 13%) of the title compound. the mixture was stirred at room temperature for 2 hr the solvent was removed by distillation under the reduced pressure The residue was purified by chromatography on silica gel by development with chloroform/methanol (91/9)

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

Procedure: 2-Fluoro-6-methoxyaniline (7.80 g) and 17.23 g of di-(2-bromoethyl)amine hydrobromide were dissolved in 5 ml of water and, by heating at about 110° C. on a bath, 10 ml of 30% potassium hydroxide solution was added thereto (each about 3.5 ml once an hour). Heating was further continued (7 hours in total). After cooled, the reaction solution was made alkaline with aqueous solution of sodium hydroxide to salt out and extracted with chloroform twice. The extract was washed with saturated sodium chloride solution, dried over sodium sulfate, the solvent was evaporated therefrom, and the residue was purified by a column chromatography to give 8.95 g of oily 1-(2-fluoro-6-methoxyphenyl)piperazine in 34.94 g yield or 94%. each about 3.5 ml once an hour Heating (7 hours in total) After cooled extracted with chloroform twice The extract was washed with saturated sodium chloride solution dried over sodium sulfate the solvent was evaporated the residue was purified by a column chromatography

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

Procedure: (2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methoxy-phenyl)-amine was prepared from 2,4,5-Trichloro-pyrimidine and 2-Fluoro-6-methoxyaniline in an analogous manner to Example 1230a. Title product was obtained as an off white solid (3.80 g, 62%). MP=133-135. LCMS 289.03 (M+H), HPLC purity=94%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.24 (s, 1H), 8.35 (s, 1H), 7.39-7.35 (m, 1H), 7.00-6.91 (m, 2H), 3.80 (s, 3H).

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

Procedure: 2-Fluoro-6-methoxyaniline (7.80 g) and 17.23 g of di-(2-bromoethyl)amine hydrobromide were dissolved in 5 ml of water and, by heating at about 110° C. on a bath, 10 ml of 30% potassium hydroxide solution was added thereto (each about 3.5 ml once an hour). Heating was further continued (7 hours in total). After cooled, the reaction solution was made alkaline with aqueous solution of sodium hydroxide to salt out and extracted with chloroform twice. The extract was washed with saturated sodium chloride solution, dried over sodium sulfate, the solvent was evaporated therefrom, and the residue was purified by a column chromatography to give 8.95 g of oily 1-(2-fluoro-6-methoxyphenyl)piperazine in 34.93 g yield or 94%. each about 3.5 ml once an hour Heating (7 hours in total) After cooled extracted with chloroform twice The extract was washed with saturated sodium chloride solution dried over sodium sulfate the solvent was evaporated the residue was purified by a column chromatography

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

Procedure: To a mixture of 2-fluoro-6-methoxyaniline (0.56 g), sodium hydrogen carbonate (0.67 g) and water (2 mL) in tetrahydrofuran (20 mL) was added a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (1.0 g) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) to give 4-chloro-N-(2-fluoro-6-methoxyphenyl)-3-nitrobenzenesulfonamide (0.56 g). This material was dissolved in N,N-dimethylformamide (15 mL). To the solution were added methyl iodide (0.15 mL) and sodium hydride (55%, 75 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give 4-chloro-N-(2-fluoro-6-methoxyphenyl)-N-methyl-3-nitrobenzenesulfonamide (0.4 g). This material was dissolved in tetrahydrofuran (3 mL). To the solution were added methanol (3 mL) and nickel(II) bromide (12 mg). To the mixture was added sodium borohydride (0.12 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/4) to give the title compound (0.3 g). the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-fluoro-6-methoxyaniline (1 equiv) in acetic acid (0.7 M) was cooled to 5° C. A mixture of bromine (0.9 equiv) in acetic acid (0.7 M) was slowly added. The reaction mixture was stirred for 2 h at 5° C. The resulting solid was filtered, washed with ether, and dried to give the title compound (90% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.84 (s, 3H) 6.79 (br. s., 2H) 6.97 (s, 1H) 7.06 (d, J=10.09 Hz, 1H). MS (ESI) m/z 219.9 [M+H]+. was slowly added The resulting solid was filtered washed with ether dried

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

Procedure: 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml.), and a solution of triphosgene (92 mg) in dichloromethane was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 3-fluoro-o-anisidine (44 μl) was added to the reaction solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 126 mg (yield 83%) of the title compound. the mixture was stirred at room temperature overnight the mixture was extracted with chloroform The chloroform layer was dried over sodium sulfate The solvent was removed by distillation under the reduced pressure The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1)

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

Procedure: (2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methoxy-phenyl)-amine was prepared from 2,4,5-Trichloro-pyrimidine and 2-Fluoro-6-methoxyaniline in an analogous manner to Example 1230a. Title product was obtained as an off white solid (3.80 g, 62%). MP=133-135. LCMS 289.03 (M+H), HPLC purity=94%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.24 (s, 1H), 8.35 (s, 1H), 7.39-7.35 (m, 1H), 7.00-6.91 (m, 2H), 3.80 (s, 3H).

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

Procedure: 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethyl-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a solution of triphosgene (92 mg) in dichloromethane was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 3-fluoro-o-anisidine (44 μl) was added to the reaction solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 126 mg (yield 83%) of the title compound. the mixture was stirred at room temperature overnight the mixture was extracted with chloroform The chloroform layer was dried over sodium sulfate The solvent was removed by distillation under the reduced pressure The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1)