Iodine → 7alpha-(5-Chloropentyl)-11beta-fluor-estr-4-ene-3,17-dione

Participants

Reaction Conditions

Reaction Steps

20% of a solution of 39 ml of 1-bromo-5-chloropentane in 300 ml of THF are first added under nitrogen to a suspension of 7.2 g of magnesium turnings in 100 ml of THF. After starting the reaction, which can be achieved by addition of iodine and dibromomethane, the remaining solution is added dropwise such that the internal temperature does not exceed 35° C. In a second flask, 51.2 g of lithium bromide are added to a suspension of 28.1 g of copper(I) iodide in 130 ml of THF at 0° C., the internal temperature rising to 40° C. 49.4 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 15 minutes. A clear solution is obtained, which is added dropwise to the Grignard solution cooled to −50° C. The mixture is then stirred at −30° C. for 15 minutes and treated dropwise at −70° C. with a solution of 25 g of 11β-fluorooestra-4,6-diene-3,17-dione in 260 ml of THF, 26 ml of 1,3-dimethyl-3,4,5,6-tetra-hydro-(1H)-pyrimidin-2-one and 59 ml of trimethyl-chlorosilane such that the internal temperature does not exceed −65° C. The mixture is stirred in the cold for 30 minutes, then 34.7 ml of glacial acetic acid are added dropwise, the cooling bath is removed and stirring is then continued 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 filtered off through Celite, then 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, 22.1 g of 7α-(5-chloropentyl)-11β-fluorooestr-4-ene-3,17-dione are obtained.

Provenance & Evidence