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0 °C

To a mixture of dimethylformamide (184 ml) and an optically active form (36.74 g) of (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid was added N-ethyldiisopropylamine (20.9 ml), and the mixture was stirred at 0° C. Thereto, diphenylphosphoryl azide (23.7 ml) was added dropwise over 30 min, and the mixture was further stirred at 0° C. for 2 hr. To the reaction mixture was added acetic acid (2.86 ml) and the mixture was warmed to room temperature. t-Butyl alcohol (96 ml) was added, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid (367 ml) was added, placed in a separatory funnel and the mixture was extracted 3 times with toluene (180 ml). The combined organic layer was successively washed with water (180 ml), 1N aqueous sodium hydroxide solution (180 ml), water (180 ml) and saturated brine (180 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue, ethanol (37 ml), tetrahydrofuran (37 ml) and 2N aqueous sodium hydroxide solution (37 ml) were mixed, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, water (180 ml) was added, and the mixture was placed in a separatory funnel, and extracted twice with toluene (180 ml). The organic layer was washed twice with water (180 ml) and once with saturated brine (180 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 8/2) to give the title compound (21.69 g, 70%).

1. stirringthe mixture was further stirred at 0° C. for 2 hr
2. temperaturethe mixture was warmed to room temperature
3. stirringthe mixture was stirred at 100° C. for 1 hr
4. temperaturecooled
5. customplaced in a separatory funnel
6. extractionthe mixture was extracted 3 times with toluene (180 ml)
7. washThe combined organic layer was successively washed with water (180 ml), 1N aqueous sodium hydroxide solution (180 ml), water (180 ml) and saturated brine (180 ml)
8. dry with materialdried over anhydrous sodium sulfate
9. filtrationfiltered
10. concentrationThe filtrate was concentrated under reduced pressure
11. additionthe obtained residue, ethanol (37 ml), tetrahydrofuran (37 ml) and 2N aqueous sodium hydroxide solution (37 ml) were mixed
12. stirringthe mixture was stirred at 60° C. for 3 hr
13. temperatureThe reaction mixture was cooled to room temperature
14. additionwater (180 ml) was added
15. customthe mixture was placed in a separatory funnel
16. extractionextracted twice with toluene (180 ml)
17. washThe organic layer was washed twice with water (180 ml) and once with saturated brine (180 ml)
18. dry with materialdried over anhydrous sodium sulfate
19. filtrationfiltered
20. concentrationThe filtrate was concentrated under reduced pressure
21. customthe obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 8/2)