1-Bromo-6-chlorohexane → 7alpha-(6-Chlorohexyl)-11beta-fluoro-estr-4-ene-3,17-dione

Participants

Reaction Conditions

Reaction Steps

30 ml of a solution of 41 ml of 1-bromo-6-chlorohexane in 270 ml of THF are first added under nitrogen to a suspension of 6.8 g of magnesium turnings in 100 ml of THF. After starting the reaction, the remaining solution is added dropwise such that the internal temperature does not exceed 35° C. In a second flask, 48.1 g of lithium bromide are added to a suspension of 4 g of copper(I) iodide in 120 ml of THF at 0° C., the internal temperature rising to 40° C. 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one are then added without cooling and the mixture is stirred at 40° C. for 30 minutes. A clear solution is obtained, which is added dropwise to the Grignard solution cooled to −40° C. The mixture is then stirred at −30° C. for 30 minutes and treated dropwise at −50° C. with a solution of 23.5 g of 11β-fluorooestra-4,6-diene-3,17-dione in 230 ml of THF, 24.6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 55 ml of trimethylchlorosilane such that the internal temperature does not exceed −40° C. The mixture is stirred in the cold for 1 h, then 32 ml of glacial acetic acid are added dropwise, the cooling bath is removed and the mixture is stirred at room temperature for 1 hour. For work-up, the reaction mixture is added to 1.5 l of water, diluted with the same amount of ethyl acetate, the precipitate is removed by means of Celite, washed with ethyl acetate, and the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium hydrogencarbonate and sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. After chromatographing the crude product on silica gel using a hexane-ethyl acetate gradient, 25.2 g of 7α-(6-chlorohexyl)-11β-fluorooestr-4-ene-3,17-dione are obtained.

Provenance & Evidence