反应详情

温度

0 °C

(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (540 mg, 7.89×10−4 mol) obtained from Example 17-(4) was dissolved in a mixed solvent (3 ml) of dichloromethane-acetonitrile (1:1). Tetrazole (112 mg, 1.6 mmol) and bis(allyloxy)(diisopropylamino)phosphine (Tetrahedron Lett., 30, 4219 (1989); 250 mg, 1.0×10−3 mol) were added thereto at 0° C., and the mixture was stirred at the same temperature for 5 minutes. The mixture was warmed to room temperature, then stirred for 30 minutes, and allyl alcohol (0.1 ml) was added thereto. The mixture was stirred for another 5 minutes, then tert-butyl hydroperoxide (ca. 5M nonane solution, 1.5 ml, ca. 7.5 mmol) was added thereto at 0° C., and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium thiosulfate were added thereto, then the mixture was stirred for 10 minutes and partitioned between ethyl acetate and water. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of ammonium chloride, and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give an oily residue. The residue was subjected to chromatography on a silica gel (15 g) column (eluent; ethyl acetate:hexane=2:1˜1:0), and further purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d.×600 mm) and JAIGEL-2H (20 mm i.d.×600 mm) connected in series for use; solvent, chloroform] to afford the title compound (363 mg, 54% yield) as a colorless amorphous solid.

1. temperatureThe mixture was warmed to room temperature
2. stirringstirred for 30 minutes
3. stirringThe mixture was stirred for another 5 minutes
4. stirringat 0° C., and the resulting mixture was stirred at room temperature for 30 minutes
5. stirringthe mixture was stirred for 10 minutes
6. custompartitioned between ethyl acetate and water
7. washThe organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate
8. dry with materiala saturated aqueous solution of ammonium chloride, and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate
9. distillationthe solvent was distilled off under reduced pressure
10. customto give an oily residue
11. customfurther purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d.×600 mm) and JAIGEL-2H (20 mm i.d.×600 mm) connected in series for use; solvent, chloroform]