4-(trifluoromethoxy)benzenethiol

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

実験手順: Zinc powder (3.1 g) was added to a suspension of p-trifluoromethoxybenzenesulfonyl chloride (1.36 ml) in concentrated sulfuric acid (3.4 ml) and water (20 ml), and the suspension was stirred at 0° C. for 18 hours and heated under reflux for 6 hours. The mixture was added with ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and saturated brine, and then concentrated under reduced pressure to give p-trifluoromethoxybenzenethiol (0.73 g, 47%). heated under reflux for 6 hours washed with water, saturated aqueous solution of sodium hydrogen carbonate, and saturated brine concentrated under reduced pressure

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

実験手順: A mixture of 3-hydroxy-1-(4-methoxybenzyl)pyrazin-2(1H)-one (2.0 g, 8.61 mmol), PyBOP (7.84 g, 15.07 mmol) and N,N-diisopropylethylamine (4.51 mL, 8 mmol) in DMF (40 mL) was stirred at RT under N2 for 3 hours whereupon 4-(trifluoromethoxy)benzenethiol (2.007 g, 10.33 mmol) was added. After having stirred for 18 additional hours, the reaction was diluted with saturated aq. NaHCO3 (65 ml) and was then extracted with EtOAc (60 ml). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 75% EtOAc/hexane) to elute 1-(4-methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (2.76 g, 6.42 mmol, 74.6% yield) as white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.58 (2H, d, J=8.78 Hz), 7.21-7.35 (4H, m), 7.02 (1H, d, J=4.52 Hz), 6.90 (2H, d, J=8.78 Hz), 6.85 (1H, d, J=4.27 Hz), 5.03 (2H, s), 3.81 (3H, s). was added was then extracted with EtOAc (60 ml) The EtOAc layer was dried over Na2SO4 concentrated The crude product was purified by silica gel chromatography

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

実験手順: 4-(Trifluoromethoxy)thiophenol (2.0 g, 10.3 mmol) was dissolved in THF (30 ml), and this solution was cooled in an ice-bath. To which sodium hydride (453 mg, 11.3 mmol) was added, and the mixture was stirred for 30 minutes. To which tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (3.66 g, 10.3 mmol) prepared in Reference Example 137 was added, and the resulting mixture was stirred at room temperature for 30 minutes, and then heated under reflux for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl chloride=20/1) to afford tert-butyl 4-(4-trifluoromethoxyphenylsulfanyl)piperidine-1-carboxylate (3.12 g, yield 80%) as a colorless oil. this solution was cooled in an ice-bath was added the resulting mixture was stirred at room temperature for 30 minutes heated under reflux for 1 hour the mixture was extracted with methylene chloride The extract was dried over magnesium sulfate filtered the filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (n-hexane/ethyl chloride=20/1)

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

実験手順: A mixture of 3-hydroxy-1-(4-methoxybenzyl)pyrazin-2(1H)-one (2.0 g, 8.61 mmol), PyBOP (7.84 g, 15.07 mmol) and N,N-diisopropylethylamine (4.51 mL, 25.8 mmol) in DMF (40 mL) was stirred at RT under N2 for 3 hours whereupon 4-(trifluoromethoxy)benzenethiol (2.007 g, 10.33 mmol) was added. After having stirred for 18 additional hours, the reaction was diluted with saturated aq. NaHCO3 (65 ml) and was then extracted with EtOAc (60 ml). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 75% EtOAc/hexane) to elute 1-(4-methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (2.76 g, 6.42 mmol, 74.6% yield) as white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.58 (2H, d, J=8.78 Hz), 7.21-7.35 (4H, m), 7.02 (1H, d, J=4.52 Hz), 6.90 (2H, d, J=8.78 Hz), 6.85 (1H, d, J=4.27 Hz), 5.03 (2H, s), 3.81 (3H, s). was added was then extracted with EtOAc (60 ml) The EtOAc layer was dried over Na2SO4 concentrated The crude product was purified by silica gel chromatography

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

実験手順: A mixture of 3-hydroxy-1-(4-methoxybenzyl)pyrazin-2(1H)-one (2.0 g, 8.61 mmol), PyBOP (7.84 g, 15.07 mmol) and N,N-diisopropylethylamine (4.51 mL, 25.8 mmol) in DMF (40 mL) was stirred at RT under N2 for 3 hours whereupon 4-(trifluoromethoxy)benzenethiol (2.007 g, 10.33 mmol) was added. After having stirred for 18 additional hours, the reaction was diluted with saturated aq. NaHCO3 (65 ml) and was then extracted with EtOAc (60 ml). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 75% EtOAc/hexane) to elute 1-(4-methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (2.76 g, 6.42 mmol, 74.6% yield) as white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.58 (2H, d, J=8.78 Hz), 7.21-7.35 (4H, m), 7.02 (1H, d, J=4.52 Hz), 6.90 (2H, d, J=8.78 Hz), 6.85 (1H, d, J=4.27 Hz), 5.03 (2H, s), 3.81 (3H, s). was added was then extracted with EtOAc (60 ml) The EtOAc layer was dried over Na2SO4 concentrated The crude product was purified by silica gel chromatography

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

実験手順: Zinc powder (3.1 g) was added to a suspension of p-trifluoromethoxybenzenesulfonyl chloride (1.36 ml) in concentrated sulfuric acid (3.4 ml) and water (20 ml), and the suspension was stirred at 0° C. for 18 hours and heated under reflux for 6 hours. The mixture was added with ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and saturated brine, and then concentrated under reduced pressure to give p-trifluoromethoxybenzenethiol (0.73 g, 47%). heated under reflux for 6 hours washed with water, saturated aqueous solution of sodium hydrogen carbonate, and saturated brine concentrated under reduced pressure

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

実験手順: Zinc powder (3.1 g) was added to a suspension of p-trifluoromethoxybenzenesulfonyl chloride (1.36 ml) in concentrated sulfuric acid (3.4 ml) and water (20 ml), and the suspension was stirred at 0° C. for 18 hours and heated under reflux for 6 hours. The mixture was added with ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and saturated brine, and then concentrated under reduced pressure to give p-trifluoromethoxybenzenethiol (0.73 g, 47%). heated under reflux for 6 hours washed with water, saturated aqueous solution of sodium hydrogen carbonate, and saturated brine concentrated under reduced pressure

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

実験手順: The title compound was prepared in 41% yield (0.66 g, colorless oil) from tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.20 g, 4.30 mmol) and 4-(trifluoromethoxy)benzenethiol (1.00 g, 5.15 mmol) by the similar manner in Step-1 of Intermediate-4.

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

実験手順: The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 4-trifluoromethoxy -thiophenol. The compound was prepared

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

実験手順: The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 4-trifluoromethoxy-thiophenol. The compound was prepared

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

実験手順: A mixture of 3-hydroxy-1-(4-methoxybenzyl)pyrazin-2(1H)-one (2.0 g, 8.61 mmol), PyBOP (7.84 g, 15.07 mmol) and N,N-diisopropylethylamine (4.51 mL, 8 mmol) in DMF (40 mL) was stirred at RT under N2 for 3 hours whereupon 4-(trifluoromethoxy)benzenethiol (2.007 g, 10.33 mmol) was added. After having stirred for 18 additional hours, the reaction was diluted with saturated aq. NaHCO3 (65 ml) and was then extracted with EtOAc (60 ml). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 75% EtOAc/hexane) to elute 1-(4-methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (2.76 g, 6.42 mmol, 74.6% yield) as white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.58 (2H, d, J=8.78 Hz), 7.21-7.35 (4H, m), 7.02 (1H, d, J=4.52 Hz), 6.90 (2H, d, J=8.78 Hz), 6.85 (1H, d, J=4.27 Hz), 5.03 (2H, s), 3.81 (3H, s). was added was then extracted with EtOAc (60 ml) The EtOAc layer was dried over Na2SO4 concentrated The crude product was purified by silica gel chromatography

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

実験手順: 4-(Trifluoromethoxy)thiophenol (2.0 g, 10.3 mmol) was dissolved in THF (30 ml), and this solution was cooled in an ice-bath. To which sodium hydride (453 mg, 11.3 mmol) was added, and the mixture was stirred for 30 minutes. To which tert-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (3.66 g, 10.3 mmol) prepared in Reference Example 137 was added, and the resulting mixture was stirred at room temperature for 30 minutes, and then heated under reflux for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl chloride=20/1) to afford tert-butyl 4-(4-trifluoromethoxyphenylsulfanyl)piperidine-1-carboxylate (3.12 g, yield 80%) as a colorless oil. this solution was cooled in an ice-bath was added the resulting mixture was stirred at room temperature for 30 minutes heated under reflux for 1 hour the mixture was extracted with methylene chloride The extract was dried over magnesium sulfate filtered the filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (n-hexane/ethyl chloride=20/1)