4-chloro-3,5-difluoroaniline

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-3,5-difluoroaniline (1.64 g, 10.0 mmol), 2-chloro-3-nitropyridine (1.56 g, 9.84 mmol) and cesium carbonate (6.56 g, 20.1 mmol) in N,N-dimethylformamide (30 mL) was stirred at 80° C. for 36 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (5×50 mL), dried over sodium sulfate, filtered, concentrated in vacuo and purified by chromatography on silica gel (Gradient: 0% to 5% ethyl acetate in petroleum ether) to provide the product as a yellow solid. Yield: 200 mg, 0.70 mmol, 7%. 1H NMR (400 MHz, CDCl3) δ 10.23 (br s, 1H), 8.55-8.61 (m, 2H), 7.52 (br d, J=9 Hz, 2H), 6.96-7.01 (m, 1H). The reaction mixture was cooled to room temperature extracted with ethyl acetate (3×200 mL) The combined organic layers were washed with saturated aqueous sodium chloride solution (5×50 mL) dried over sodium sulfate filtered concentrated in vacuo purified by chromatography on silica gel (Gradient: 0% to 5% ethyl acetate in petroleum ether)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-3,5-difluoroaniline (1.64 g, 10.0 mmol), 2-chloro-3-nitropyridine (1.56 g, 9.84 mmol) and cesium carbonate (6.56 g, 20.1 mmol) in N,N-dimethylformamide (30 mL) was stirred at 80° C. for 36 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (5×50 mL), dried over sodium sulfate, filtered, concentrated in vacuo and purified by chromatography on silica gel (Gradient: 0% to 5% ethyl acetate in petroleum ether) to provide the product as a yellow solid. Yield: 200 mg, 0.70 mmol, 7%. 1H NMR (400 MHz, CDCl3) δ 10.23 (br s, 1H), 8.55-8.61 (m, 2H), 7.52 (br d, J=9 Hz, 2H), 6.96-7.01 (m, 1H). The reaction mixture was cooled to room temperature extracted with ethyl acetate (3×200 mL) The combined organic layers were washed with saturated aqueous sodium chloride solution (5×50 mL) dried over sodium sulfate filtered concentrated in vacuo purified by chromatography on silica gel (Gradient: 0% to 5% ethyl acetate in petroleum ether)

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

Procedure: Compound (250) can be prepared in the same manner as in Preparation Example 240, except for replacing compound (P102) with 4-chloro-3,5-difluorophenol. The 4-chloro-3,5-difluorophenol can be prepared by reacting a Grignard reagent prepared from 1-bromo-4-chloro-3,5-difluorobenzene with t-butyl hydroperoxide or converting the same Grignard reagent to a boric ester, and oxidizing the product with hydrogen peroxide under a basic condition. It is also prepared by nitrating 2-chloro-1,3-difluorobenzene (obtainable by decomposing a diazonium salt of 2,6-difluoroaniline in the presence of cuprous chloride or in hydrochloric acid), reducing the nitro-compound to obtain 4-chloro-3,5-difluoroaniline, and decomposing its diazonium salt in sulfuric acid.

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

Procedure: Compound (250) can be prepared in the same manner as in Preparation Example 240, except for replacing compound (P102) with 4-chloro-3,5-difluorophenol. The 4-chloro-3,5-difluorophenol can be prepared by reacting a Grignard reagent prepared from 1-bromo-4-chloro-3,5-difluorobenzene with t-butyl hydroperoxide or converting the same Grignard reagent to a boric ester, and oxidizing the product with hydrogen peroxide under a basic condition. It is also prepared by nitrating 2-chloro-1,3-difluorobenzene (obtainable by decomposing a diazonium salt of 2,6-difluoroaniline in the presence of cuprous chloride or in hydrochloric acid), reducing the nitro-compound to obtain 4-chloro-3,5-difluoroaniline, and decomposing its diazonium salt in sulfuric acid.

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

Procedure: Compound (250) can be prepared in the same manner as in Preparation Example 240, except for replacing compound (P102) with 4-chloro-3,5-difluorophenol. The 4-chloro-3,5-difluorophenol can be prepared by reacting a Grignard reagent prepared from 1-bromo-4-chloro-3,5-difluorobenzene with t-butyl hydroperoxide or converting the same Grignard reagent to a boric ester, and oxidizing the product with hydrogen peroxide under a basic condition. It is also prepared by nitrating 2-chloro-1,3-difluorobenzene (obtainable by decomposing a diazonium salt of 2,6-difluoroaniline in the presence of cuprous chloride or in hydrochloric acid), reducing the nitro-compound to obtain 4-chloro-3,5-difluoroaniline, and decomposing its diazonium salt in sulfuric acid.

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

Procedure: Compound (250) can be prepared in the same manner as in Preparation Example 240, except for replacing compound (P102) with 4-chloro-3,5-difluorophenol. The 4-chloro-3,5-difluorophenol can be prepared by reacting a Grignard reagent prepared from 1-bromo-4-chloro-3,5-difluorobenzene with t-butyl hydroperoxide or converting the same Grignard reagent to a boric ester, and oxidizing the product with hydrogen peroxide under a basic condition. It is also prepared by nitrating 2-chloro-1,3-difluorobenzene (obtainable by decomposing a diazonium salt of 2,6-difluoroaniline in the presence of cuprous chloride or in hydrochloric acid), reducing the nitro-compound to obtain 4-chloro-3,5-difluoroaniline, and decomposing its diazonium salt in sulfuric acid.