反应详情

温度

82 °C

Nitrogen atmosphere was applied during the reaction. Zinc dust (1.29 g; 19.76 mmol; 2.66 equiv.) and 2-methyl-THF (14 mL) were charged to a flask and cooled to below −5° C. TiCl4 (1.1 mL; 10.03 mmol; 1.35 equiv.) was slowly added (over 20 minutes; as the addition is exothermic) to the zinc-slurry, maintaining the temperature below 0° C. The reaction mixture was heated to reflux (82° C.) and refluxed for 2 hrs. A prepared solution of both ketones (1.80 g of 4-(2-hydroxyethoxy)benzophenone (see (A) above); 7.43 mmol; 1 equiv.; 1.25 g of 3-chloropropiophenone; 7.43 mmol; 1 equiv) in 2-methyl-THF (5 mL) was slowly added to the black reaction mixture at reflux. The temperature rose to 85° C. The reaction mixture was refluxed for 2 hours. The reaction mixture was then cooled to room temperature. 4.6 mL of 1M HCl and 4.2 mL of 6 M HCl were added and the mixture stirred for 10 minutes. Then 13 mL toluene was added and the reaction mixture was stirred for 15 min. The layers were separated. The toluene layer was washed with 4 mL water and dried over MgSO4. Quantitative HPLC from toluene solution shows 38% yield and the ratio of Z/E isomers of Ospemifene 4.3/1. The toluene solution was washed with 8.5 mL conc. NaHCO3, 6 mL water and dried over MgSO4. 3.05 g of crude product was obtained after concentration on a rotavapor (bath 34° C.). Crystallization in methanol (13 mL) and water (2.5 mL) gave an oil. This solution was heated until it was a clear solution and then let to cool slowly to room temperature (crystals appeared) and then left to stand overnight at +8° C. The crystals were filtered, rinsed with 60% MeOH/water and dried. 0.787 g of light yellow solid was obtained, at 92.8% purity by HPLC (area %), and a yield of 26% (calculated as pure product).

1. customNitrogen atmosphere was applied during the reaction
2. temperaturecooled to below −5° C
3. additionas the addition
4. temperaturemaintaining the temperature below 0° C
5. temperatureThe reaction mixture was heated
6. temperaturerefluxed for 2 hrs
7. temperatureat reflux
8. customrose to 85° C
9. temperatureThe reaction mixture was refluxed for 2 hours
10. temperatureThe reaction mixture was then cooled to room temperature
11. stirringthe reaction mixture was stirred for 15 min
12. customThe layers were separated
13. washThe toluene layer was washed with 4 mL water
14. dry with materialdried over MgSO4
15. washThe toluene solution was washed with 8.5 mL conc. NaHCO3, 6 mL water
16. dry with materialdried over MgSO4
17. custom3.05 g of crude product was obtained
18. concentrationafter concentration on a rotavapor (bath 34° C.)
19. customCrystallization in methanol (13 mL)
20. customwater (2.5 mL) gave an oil
21. temperatureThis solution was heated until it
22. temperatureto cool slowly to room temperature (crystals appeared)
23. waitleft
24. waitto stand overnight at +8° C
25. filtrationThe crystals were filtered
26. washrinsed with 60% MeOH/water
27. customdried