Hydrochloric Acid → Ospemifene

Participants

Reaction Conditions

Reaction Steps

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).

Provenance & Evidence