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

Temperature

40 °C

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.

1. customthe reaction, which
2. additionthe remaining solution is added dropwise such that the internal temperature
3. customdoes not exceed 35° C
4. customrising to 40° C
5. temperaturewithout cooling
6. customA clear solution is obtained
7. additionwhich is added dropwise to the Grignard solution
8. temperaturecooled to −50° C
9. stirringThe mixture is then stirred at −30° C. for 15 minutes
10. customdoes not exceed −65° C
11. stirringThe mixture is stirred in the cold for 30 minutes
12. customthe cooling bath is removed
13. stirringstirring
14. waitis then continued at room temperature for 1 hour
15. additionFor work-up, the reaction mixture is added to 1.5 l of water
16. additiondiluted with the same amount of ethyl acetate
17. filtrationthe precipitate is filtered off through Celite
18. washwashed with ethyl acetate
19. extractionthe aqueous phase is extracted 3 times with ethyl acetate
20. washwashed with sodium hydrogencarbonate and sodium chloride solution
21. dry with materialdried over magnesium sulphate
22. concentrationconcentrated in vacuo
23. customare obtained

ORD record

ord-b46c3152104444d79cac6d8b20725035

Source dataset

uspto-grants-2004_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06677324B1