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To a solution of 1-bromo-4-(ethylsulfonyl)benzene (1.50 g) in 1,4-dioxane (20 mL) were added diethyl malonate (1.16 g), potassium phosphate (3.84 g), biphenyl-2-yl(di-tert-butyl)phosphine (108 mg) and palladium acetate (II) (40 mg). The reaction solution was purged with argon, and the mixture was heated under reflux for 12 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50, volume ratio) to give a colorless oil. A solution of the obtained oil in N,N-dimethylformamide (20 mL) was purged with nitrogen, sodium hydride (60%, oil, 213 mg) was added under ice-cooling, and the mixture was stirred at 0° C. for 15 min. To the reaction solution was added a solution of 4-(iodomethyl)tetrahydro-2H-pyran (1.15 g) in N,N-dimethylformamide (10 mL) at 0° C., and the mixture was stirred for 3 hr at 90° C. The reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=10:90-40:60, volume ratio) to give a colorless oil. To a solution of the obtained oil in a mixed solvent of tetrahydrofuran (40 mL) and methanol (20 mL) was added 2M aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 60° C. for 3 hr. The reaction solution was cooled to room temperature, and acidified with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (1.33 g, yield 67%) as colorless crystals. MS: 327 (MH+).

1. customThe reaction solution was purged with argon
2. temperaturethe mixture was heated
3. temperatureunder reflux for 12 hr
4. additionA saturated aqueous ammonium chloride solution was added to the reaction mixture
5. extractionthe mixture was extracted with ethyl acetate
6. washThe extract was washed successively with water and saturated brine
7. dry with materialdried over anhydrous magnesium sulfate
8. concentrationconcentrated under reduced pressure
9. customThe residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50, volume ratio)
10. customto give a colorless oil
11. customA solution of the obtained oil in N,N-dimethylformamide (20 mL) was purged with nitrogen, sodium hydride (60%, oil, 213 mg)
12. additionwas added under ice-
13. temperaturecooling
14. additionTo the reaction solution was added a solution of 4-(iodomethyl)tetrahydro-2H-pyran (1.15 g) in N,N-dimethylformamide (10 mL) at 0° C.
15. stirringthe mixture was stirred for 3 hr at 90° C
16. concentrationThe reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution
17. additionwas added to the residue
18. extractionthe mixture was extracted with ethyl acetate
19. washThe extract was washed successively with water and saturated brine
20. dry with materialdried over anhydrous magnesium sulfate
21. concentrationconcentrated under reduced pressure
22. customThe residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=10:90-40:60, volume ratio)
23. customto give a colorless oil
24. stirringthe mixture was stirred at 60° C. for 3 hr
25. temperatureThe reaction solution was cooled to room temperature
26. extractionthe mixture was extracted with ethyl acetate
27. washThe extract was washed successively with water and saturated brine
28. dry with materialdried over anhydrous magnesium sulfate
29. concentrationconcentrated under reduced pressure
30. customThe residue was recrystallized from hexane-ethyl acetate