1-bromo-4-[bromo(difluoro)methyl]benzene

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: Under exclusion of oxygen, a solution of 14.0 g (67.63 mmol) of 1-bromo-4-(difluoromethyl)benzene (CAS 51776-71-7) and 25.3 g (142 mmol) of N-bromosuccinimide (NBS) in 190 ml of carbon tetrachloride is irradiated using a daylight lamp. During the radiation, the solvent reaches its boiling point. The mixture is irradiated under reflux for 24 hours. The mixture is then allowed to cool to room temperature, and precipitated succinimide is filtered off. Another 25 g of NBS are added to the filtrate, and the mixture is once more, under exclusion of oxygen, irradiated under reflux for 24 hours. After cooling, the mixture is again filtered and the filtrate is evaporated to dryness. This gives 18 g of a dark orange oil which is purified by vacuum distillation at 13 torr. This gives 12.7 g (44.4 mmol, 66% yield) of a colorless oil. The mixture is irradiated under reflux for 24 hours precipitated succinimide is filtered off Another 25 g of NBS are added to the filtrate irradiated under reflux for 24 hours After cooling the mixture is again filtered the filtrate is evaporated to dryness This gives 18 g of a dark orange oil which is purified by vacuum distillation at 13 torr

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

実験手順: Under exclusion of oxygen, a solution of 14.0 g (67.63 mmol) of 1-bromo-4-(difluoromethyl)benzene (CAS 51776-71-7) and 25.3 g (142 mmol) of N-bromosuccinimide (NBS) in 190 ml of carbon tetrachloride is irradiated using a daylight lamp. During the radiation, the solvent reaches its boiling point. The mixture is irradiated under reflux for 24 hours. The mixture is then allowed to cool to room temperature, and precipitated succinimide is filtered off. Another 25 g of NBS are added to the filtrate, and the mixture is once more, under exclusion of oxygen, irradiated under reflux for 24 hours. After cooling, the mixture is again filtered and the filtrate is evaporated to dryness. This gives 18 g of a dark orange oil which is purified by vacuum distillation at 13 torr. This gives 12.7 g (44.4 mmol, 66% yield) of a colorless oil. The mixture is irradiated under reflux for 24 hours precipitated succinimide is filtered off Another 25 g of NBS are added to the filtrate irradiated under reflux for 24 hours After cooling the mixture is again filtered the filtrate is evaporated to dryness This gives 18 g of a dark orange oil which is purified by vacuum distillation at 13 torr

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

実験手順: Under exclusion of oxygen, a solution of 14.0 g (67.63 mmol) of 1-bromo-4-(difluoromethyl)benzene (CAS 51776-71-7) and 25.3 g (142 mmol) of N-bromosuccinimide (NBS) in 190 ml of carbon tetrachloride is irradiated using a daylight lamp. During the radiation, the solvent reaches its boiling point. The mixture is irradiated under reflux for 24 hours. The mixture is then allowed to cool to room temperature, and precipitated succinimide is filtered off. Another 25 g of NBS are added to the filtrate, and the mixture is once more, under exclusion of oxygen, irradiated under reflux for 24 hours. After cooling, the mixture is again filtered and the filtrate is evaporated to dryness. This gives 18 g of a dark orange oil which is purified by vacuum distillation at 13 torr. This gives 12.7 g (44.4 mmol, 66% yield) of a colorless oil. Boiling point (13 torr): 90-92° C. The mixture is irradiated under reflux for 24 hours precipitated succinimide is filtered off Another 25 g of NBS are added to the filtrate irradiated under reflux for 24 hours After cooling the mixture is again filtered the filtrate is evaporated to dryness This gives 18 g of a dark orange oil which is purified by vacuum distillation at 13 torr

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

実験手順: A suspension of 1.17 g (8.23 mmol) of 4-fluoro-2-(hydroxymethyl)phenol from Example 34A, 2.59 g (12.63 mmol) of 1-bromo-4-[bromo(difluoro)methyl]benzene from Example 33A and 1.25 g (9.06 mmol) of potassium carbonate in 10 ml of 2-propanol is heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is suspended in methylene chloride, absorbed on silica gel, dried in vacuo and purified by chromatography (mobile phase: cyclohexane/ethyl acetate 10:1, then 100% ethyl acetate). 1.02 g (2.95 mmol, 35% yield) of the title compound are obtained. is heated to reflux for 12 hours The mixture is then concentrated to dryness absorbed on silica gel dried in vacuo purified by chromatography (mobile phase

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

実験手順: With exclusion of oxygen, a solution of 14.0 g (67.63 mmol) of 1-bromo-4-(difluoromethyl)benzene [CAS 51776-71-7] and 25.3 g (142 mmol) of N-bromosuccinimide (NBS) in 190 ml of tetrachloromethane is irradiated with a sun lamp. During this, the solvent reaches its boiling point. It is irradiated under reflux for 24 hours. The mixture is then allowed to cool to room temperature and precipitated succinimide is filtered off. The filtrate is again mixed with 25 g of NBS and irradiated once more with exclusion of oxygen under reflux for 24 hours. Cooling is followed by filtration again, and the filtrate is concentrated to dryness. 18 g of an orange-colored oil are obtained as crude product, which is purified further by vacuum distillation at 13 mmHg. 12.7 g (44.4 mmol, 66% yield) of a colorless oil are obtained. It is irradiated under reflux for 24 hours precipitated succinimide is filtered off The filtrate is again mixed with 25 g of NBS irradiated once more with exclusion of oxygen under reflux for 24 hours Cooling is followed by filtration again the filtrate is concentrated to dryness

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

実験手順: To a cooled (0° C.) solution of the title compound from Example 1 Step B (515 mg, 1.37 mmol) in DMF (5 mL) was added NaH (35.0 mg, 1.46 mmol). The reaction vessel was then allowed to warm to ambient temperature for 25 min, followed by addition of 1-bromo-4-[bromo(difluoro)methyl]benzene (445 mg, 1.56 mmol, synthesized according to U.S. Pat. No. 6,939,990) and heated at 60° C. After 24 h, the reaction mixture was cooled, quenched by addition of 2 N HCl and extracted with hexane-EtOAc. Purification by silica gel flash chromatography (5% EtOAc in hexanes to 10% EtOAc in hexanes) yielded the title compound: LCMS m/z 564.1 [M−F]+; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.88-7.82 (m, 2H), 7.78 (d, J=7.1 Hz, 1H), 7.57 (dd, J=7.8, 0.7 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.46-7.41 (m, 2H), 7.39-7.32 (m, 3H), 4.37 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H). synthesized 6,939,990) and heated at 60° C the reaction mixture was cooled quenched by addition of 2 N HCl extracted with hexane-EtOAc Purification by silica gel flash chromatography (5% EtOAc in hexanes to 10% EtOAc in hexanes)

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

実験手順: Under exclusion of oxygen, a solution of 14.0 g (67.63 mmol) of 1-bromo-4-(difluoromethyl)benzene (CAS 51776-71-7) and 25.3 g (142 mmol) of N-bromosuccinimide (NBS) in 190 ml of carbon tetrachloride is irradiated using a daylight lamp. During the radiation, the solvent reaches its boiling point. The mixture is irradiated under reflux for 24 hours. The mixture is then allowed to cool to room temperature, and precipitated succinimide is filtered off. Another 25 g of NBS are added to the filtrate, and the mixture is once more, under exclusion of oxygen, irradiated under reflux for 24 hours. After cooling, the mixture is again filtered and the filtrate is evaporated to dryness. This gives 18 g of a dark orange oil which is purified by vacuum distillation at 13 torr. This gives 12.7 g (44.4 mmol, 66% yield) of a colorless oil. The mixture is irradiated under reflux for 24 hours precipitated succinimide is filtered off Another 25 g of NBS are added to the filtrate irradiated under reflux for 24 hours After cooling the mixture is again filtered the filtrate is evaporated to dryness This gives 18 g of a dark orange oil which is purified by vacuum distillation at 13 torr